Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

ABSTRACT

The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

FIELD OF THE INVENTION

This invention relates to therapeutic compounds and compositions, andmethods for their use in the treatment of various indications, includingvarious cancers. In particular, the invention relates to therapies andmethods of treatment for cancers such as prostate cancer.

BACKGROUND OF THE INVENTION

Prostate cancer is the most commonly diagnosed malignancy in males inthe United States and the second leading cause of male cancer mortality.Numerous studies have shown that the androgen receptor (AR) is centralnot only to the development of prostate cancer, but also the progressionof the disease to the castration resistance state (Taplin, M. E. et al.,J. Clin. Oncol. 2003 21:2673-8; and Tilley, W. D. et al., Cancer Res.1994 54:4096-4102). Thus, effective inhibition of human AR remains oneof the most effective therapeutic approaches to the treatment ofadvanced, metastatic prostate cancer.

Androgens are also known to play a role in female cancers. One exampleis ovarian cancer where elevated levels of androgens are associated withan increased risk of developing ovarian cancer (Helzlsouer, K. J. etal., JAMA 1995 274, 1926-1930; Edmondson, R. J. et al., Br. J. Cancer2002 86, 879-885). Moreover, AR has been detected in a majority ofovarian cancers (Risch, H. A., J. Natl. Cancer Inst. 1998 90, 1774-1786;Rao, B. R. et al., Endocr. Rev. 1991 12, 14-26; Clinton, G. M. et al.,Crit. Rev. Oncol. Hematol. 1997 25, 1-9).

AR belongs to the nuclear hormone receptor family that is activated byandrogens such as testosterone and dihydrotestosterone. These androgens,as well as antagonists such as enzalutamide, compete with the androgensthat bind to the ligand binding domain (LBD). AR possesses a modularorganization characteristic of all nuclear receptors. It is comprised ofan N-terminal domain (NTD), a central DNA binding domain (DBD), a shorthinge region, and C-terminal domain that contains a hormone ligandbinding pocket (the LBD, which also comprises the hormone binding site(HBS)) and the Activation Function-2 (AF2) site (Gao, W. Q. et al, Chem.Rev. 2005 105:3352-3370). The latter represents a hydrophobic groove onthe AR surface which is flanked with regions of positive and negativecharges—“charge clamps” that are significant for binding AR activationfactors (Zhou, X. E. et al., J. Biol. Chem. 2010 285:9161-9171).

The activation of AR follows a well characterized pathway: in thecytoplasm, the receptor is associated with chaperone proteins thatmaintain agonist binding conformation of the AR (Georget, V. et al.,Biochemistry 2002 41:11824-11831). Upon binding of an androgen, the ARundergoes a series of conformational changes, disassociation fromchaperones, dimerization, and translocation into the nucleus (Fang, Y.F. et al., J. Biol. Chem. 1996 271:28697-28702; and Wong, C. I. et al.,J. Biol. Chem. 1993 268:19004-19012) where it further interacts withco-activator proteins at the AF2 site (Zhou, X. E. et al. J. Biol. Chem.2010 285:9161-9171). This event triggers the recruitment of RNApolymerase II and other factors to form a functional transcriptionalcomplex with the AR.

In castration-resistant prostate cancer (CRPC), drug resistance canmanifest through AR-LBD mutations that convert AR-antagonists intoagonists or by expression of AR-variants lacking the LBD. AR is a majordriver of prostate cancer and inhibition of its transcriptional activityusing competitive antagonists such as enzalutamide and apalutamideremains a frontline therapy for prostate cancer management. Anothertherapy is abiraterone which is an inhibitor of cytochrome P450 17A1that impairs AR signaling by depleting adrenal and intratumoraltestosterone and dihydrotestosterone. Recent work (Antonarakis, E. S. etal., New Engl. J. Med. 2014 37, 1028-1038) has shown that patients onenzalutamide and abiraterone with a splice variant of AR, labelled asAR-V7, had lower PSA response rates, shorter PSA progression-freesurvival, and shorter overall survival.

AR-V7 lacks the LBD, which is the target of enzalutamide andtestosterone, but AR-V7 remains constitutively active as a transcriptionfactor. Accordingly, it is desirable to investigate other approaches toantagonize the AR receptor as well as AR-V7. The common domain betweenthese two proteins is the DBD and compounds have been identified asdiscussed in Li, H. et al., J. Med. Chem. 2014 57, 6458-6467 (2014):Dalal, K. et al., Mol. Cancer Ther. 2017 vol. 16, 2281-2291; Xu, R. etal., Chem. Biol. & Drug Design 2018 91(1), 172-180; and WO 2015/120543.

Several methods are available for the manipulation of protein levels,including bi-functional proteolysis targeting chimeric molecules(PROTACs) which contain a ligand that recognizes the target protein thatis linked to a ligand that binds to a specific E3 ubiquitin ligase. Theensuing bifunctional molecule binds to the target protein and the E3ligase enabling the transfer of ubiquitin to the target protein from theLigase provided there is a suitable acceptor on the target protein.Another method is the “molecular glue” process whereby the moleculetogether with the E3 ligase recruit the target protein to the E3 ligasefollowed by the ubiquitin transfer and degradation of the target(Chopra, R., Sadok, A., Collins, I., Drug Disc Today: Technologies,2019, 31, 5-13.) In the case of a compound acting as a “molecular glue”,the only requirement is the presence of an E3 ligase binding moiety.After binding to the E3 ligase, the ensuing moiety could recruit theprotein to be degraded. The labelling of proteins with ubiquitin isimplicated in the protein's turnover by the 26S proteasome.

Protein ubiquitination is a multi-step process whereby a ubiquitinprotein is successively relayed between different classes of enzymes(E1, E2, E3) in order to eventually tag a cellular substrate. Initially,the C-terminal carboxylate of ubiquitin is adenylated by the E1activating enzyme in an ATP-dependent step. Subsequently, a conservednucleophilic cysteine residue of the E1 enzyme displaces the AMP fromthe ubiquitin adenylate resulting in a covalent ubiquitin thioesterconjugate. The binding and ensuing adenylation of a second ubiquitinmolecule promote the recruitment of an E2 conjugating enzyme to thisternary complex. An active site Cys on the E2 subsequently facilitatesthe transfer of the covalently linked ubiquitin from the E1 to a Cysresidue on the E2 through a trans-thioesterification reaction.Concomitantly, an E3 ligase recruits a specific downstream targetprotein and mediates the transfer of the ubiquitin from the E2 enzyme tothe terminal substrate through either a covalent or non-covalentmechanism. Each ubiquitin is ligated to a protein through either apeptide bond with the N-terminal amino group or an isopeptide bondformed between a side chain ε-amino group of a select Lys residue on thetarget protein and the ubiquitin.

Deubiquitinating enzymes (DUBs) are enzymes that specifically cleave theubiquitin protein from the substrate thereby offering additionalmechanisms of regulation over the entire labeling pathway. In thecurrent human proteome there are eight known human E1s, about 40 E2s,over 600 E3s and over 100 DUBs. These enzymes are well described inPavia, S. et al., J. Med. Chem. 2018 61(2), 405-421.

The E3 ligases originate in three major classes—the RING finger andU-box E3s, the HECT E3s, and the RING/HECT-hybrid type E3s. The E3ligases are localized in various cell organelles and hence theeffectiveness of the E3 ligase ligand depends at least in part on thelocation of the protein targeted for degradation, assuming that the fullmolecule is available within the appropriate location in the cell. Inaddition, for every combination of the target ligand and the ubiquitinrecruiting ligand, the linker length and conformational flexibility alsocontributes to the effectiveness of the degradation molecule. Themechanism depends on the availability of a Lys residue on the surface ofthe protein close to the targeted protein ligand binding pocket.Ubiquitin binds at Lys residues and hence the “delivery” of ubiquitinfor binding at the appropriate Lys influences the effectiveness of thedegradation molecule. Crew et al. (US20170327469A1, US20180099940A1) areprogressing a proposed treatment for castration-resistant prostatecancer based on bifunctional molecules coupling various E3 ligases to ARantagonists binding at the AR LBD site. Our approach is different inthat we do not target the LBD site but the DBD site and,correspondingly, the chemical matter is quite different.

There exists a continuing need for effective treatments for diseases andconditions that are related to aberrant AR regulation or activity, forexample, cancers such as prostate cancer, and Kennedy's Disease. Indeveloping such treatments, it would be desirable to have a moleculewhich can simultaneously bind AR and an E3 ubiquitin ligase and whichalso promotes ubiquitination of AR-V7 and perhaps AR, and leads todegradation of AR-V7 and AR by the proteasome.

SUMMARY OF THE INVENTION

The present invention relates to bi-functional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods for using same. More specifically, the presentdisclosure provides specific proteolysis targeting chimera (PROTAC)molecules which find utility as modulators of targeted ubiquitinizationof a variety of polypeptides and other proteins, such as AR, which arethen degraded and/or otherwise inhibited by the compounds as describedherein.

In one aspect, these PROTAC molecules comprise an E3 ubiquitin ligasebinding moiety (i.e., a ligand for an E3 ubiquitin ligase) linked to amoiety that binds a target protein (i.e., a protein/polypeptidetargeting ligand) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and/orinhibition) of that protein. In addition, the description providesmethods for using an effective amount of the compounds described hereinfor the treatment or amelioration of a disease condition includingcancer, e.g., prostate cancer, and Kennedy's Disease.

Suitable ligands that bind to the E3 ubiquitin ligase include cereblonbinders such as immunomodulatory imide drugs (IMiDs) includingthalidomide, pomalidomide, and lenalidomide (Deshales, R. J., NatureChem Biol. 2015 11, 634-635), and analogs or derivatives thereof. TheIMiDs themselves act as “molecular glues” and therefore have been shownto recruit a different set of proteins for degradation (reference). Inaddition, we have uncovered an intermediate molecule that acts via the“molecular glue” mechanism. Other suitable E3 ubiquitin ligase bindersare E3 CRL2^(VHL) compounds, also called Von-Hippel-Lindau or VHLligands, the cellular inhibitor of apoptosis protein (IAP) as discussedin Shibata, N. et al., J. Med. Chem., 2018 61(2), 543-575. Binders ofthe E3 ligase Mouse Double Minute 2 (MDM2) comprise the fourth class ofE3 Ligase Binders (E3LBs) that are utilized (Skalniak, L., et al.,Expert Opin. Ther, Patents, 2019, 29, 151-170).

In one aspect, there are provided compositions comprising such compoundswhich function to recruit proteins including AR-V7 and AR for targetedubiquitination and degradation. In some embodiments, the structure ofsuch compounds can be depicted as:

ARB-E3LB

wherein ARB is an AR binding moiety and E3LB is a ubiquitin ligasebinding moiety.

In some embodiments, the compounds may further comprise a chemicallinker (“L”). The structure of such compounds can be depicted as:

ARB-L-E3LB

wherein ARB is an AR binding moiety, L is a bond or linker moiety, andE3LB is a ubiquitin ligase binding moiety.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or pharmaceutically acceptable salt form thereof, and apharmaceutically acceptable carrier. The therapeutic compositionsmodulate protein degradation in a patient or subject, for example, ananimal such as a human, and can be used for treating or amelioratingdisease states or conditions which are modulated through the degradedprotein. In certain embodiments, the therapeutic compositions asdescribed herein may be used to effectuate the degradation and/orinhibition of proteins of interest for the treatment or amelioration ofa disease, e.g., cancer.

In another aspect, the present disclosure provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bi-functional compoundas described herein comprising an ARB moiety and a E3LB moiety,preferably linked through a linker moiety, as otherwise describedherein, wherein the E3LB moiety is coupled to the ARB moiety and whereinthe E3LB moiety recognizes an E3 ubiquitin ligase and the ARB moietyrecognizes the target protein such that degradation of the targetprotein occurs when the target protein is placed in proximity to theubiquitin ligase, thus resulting in degradation/inhibition of theeffects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cells ofa patient.

In another aspect, the description provides methods for treating orameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a pharmaceutical composition comprising aneffective amount, e.g., a therapeutically effective amount, of acompound as described herein or pharmaceutically acceptable salt formthereof, and a pharmaceutically acceptable carrier, wherein thecomposition is effective for treating or ameliorating the disease ordisorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the invention may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional advantages objects and embodimentsare expressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the invention, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference. Where applicable or not specifically disclaimed, any one ofthe embodiments described herein are contemplated to be able to combinewith any other one or more embodiments, even though the embodiments aredescribed under different aspects of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an immunoblot of certain exemplified compounds.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present invention. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

The present description relates to the surprising and unexpecteddiscovery that an E3 ubiquitin ligase protein can ubiquitinate a targetprotein, in particular the androgen receptor of a slice variant of ARwhich lacks the LBD, labelled as AR-V7, once the E3 ubiquitin ligaseprotein and the target protein are brought into proximity by a chimericconstruct (e.g., a PROTAC) as described herein, in which a moiety thatbinds the E3 ubiquitin ligase protein is coupled, e.g., covalently, to amoiety that binds the androgen receptor target protein. Accordingly, thepresent description provides compounds, compositions comprising thesame, and associated methods of use for ubiquitination and degradationof a chosen target protein, e.g., androgen receptor AR-V7.

In one aspect, the present disclosure provides compounds useful forregulating protein activity. The composition comprises a ubiquitinpathway protein binding moiety (preferably for an E3 ubiquitin ligase,alone or in complex with an E2 ubiquitin conjugating enzyme which isresponsible for the transfer of ubiquitin to targeted proteins)according to a defined chemical structure and a protein targeting moietywhich are linked or coupled together, preferably through a linker,wherein the ubiquitin pathway protein binding moiety recognizes aubiquitin pathway protein and the targeting moiety recognizes a targetprotein (e.g., androgen receptor). Such compounds may be referred toherein as PROTAC compounds or PROTACs.

in one aspect, the PROTACs of the present invention comprise an E3ubiquitin ligase binding moiety (“E3LB”), and a moiety that binds atarget protein (i.e. a protein/polypeptide targeting ligand) that is anAR binding moiety (“ARB”). In this embodiment, the structure of thebi-functional compound can be depicted as:

ARB-E3LB

where ARB is an AR binding moiety as described herein, and E3LB is an E3ligase binding moiety as described herein

In certain embodiments the bi-functional compound further comprises achemical linker (“L”). In these embodiments, the structure of thebi-functional compounds can be depicted as:

ARB-L-E3LB

where ARB is an AR binding moiety as described herein, E3LB is an E3ligase binding moiety as described herein, and L is a chemical linkermoiety, e.g., a linker as described herein, or optionally a bond, thatlinks the ARB and E3LB moieties.

The respective positions of the ARB and E3LB moieties as well as theirnumber as illustrated herein is provided by way of example only and isnot intended to limit the compounds in any way. As would be understoodby the skilled artisan, the bi-functional compounds as described hereincan be synthesized such that the number and position of the respectivefunctional moieties can be varied as desired. In certain embodiments,the compounds as described herein comprise multiple E3LB moieties,multiple ARB moieties, multiple chemical linkers, or a combinationthereof.

It will be understood that the general structures are exemplary and therespective moieties can be arranged spatially in any desired order orconfiguration, e.g., ARB-L-E3LB, and E3LB-L-ARB, respectively. The E3LBgroup and ARB group may be covalently linked to the linker group throughany covalent bond which is appropriate and stable to the chemistry ofthe linker. It will be further understood that for all compoundsdescribed herein, one or more hydrogen atoms may be replaced with anequivalent number of deuterium atoms.

In certain embodiments, the ARB may be selected from the followingstructures:

wherein L is the linker in the general formula above;

A is 3-7 membered alicyclic with 0-4 heteroatoms or aryl, heteroarylindependently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH,NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1 or more halo),CH₂F, CHF₂, CF₃, C₁₋₆ alkyl (linear, branched, optionally substituted by1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched,optionally substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl,3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or morehalo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, or C₂₋₆ alkynyl;

B is aryl, heteroaryl independently substituted by 1 or more halo,hydroxyl, nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionallysubstituted by 1 or more halo), CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms andsubstituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₄alkyl (linear, branched, optionally substituted by 1 or more halo, C₁₋₆alkoxy), C₁₋₆ alkoxy (linear, branched, optionally substituted by 1 ormore halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the linker L isattached to B; and

R¹ are independently H, OH, CONH₂, CONR²R³, SONH₂, SONR²R³, SO₂NH₂,SO₂NR²R³, NHCO C₁₋₃ alkyl (optionally substituted by 1 or more halo),NR²COC₁₋₃ alkyl (optionally substituted by 1 or more halo), NR²SO₂C₁₋₃alkyl (optionally substituted by 1 or more halo), NR²SOC₁₋₃ alkyl(optionally substituted by 1 or more halo), CN, C≡CH, NH₂, NR²R³, OCH₃,OC₁₋₃ alkyl (optionally substituted by 1 or more halo), CHF₂, CH₂F, CF₃,halo, C₁₋₆ alkyl (linear, branched, optionally substituted by 1 or morehalo, C₁₋₆ alkoxyl) or, if applicable, taken together with an R¹ on anadjacent bonded atom, together with the atoms they are attached to, forma 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2heteroatoms, and R², R³ is independently H, halo, C₁₋₆ alkyl (optionallysubstituted by 1 or more F) or taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms.

In one aspect, A is:

wherein R¹ is described above.

In another aspect, A is:

wherein R¹ is described above and X═C or N.

In yet another aspect, B is:

wherein L is the linker as described above, and R¹ is described above.

In still another aspect, B is:

wherein L is the linker as described above, and R¹ is described above.

In yet another aspect, B is:

wherein L is the linker as described above, and R¹ is described above.

The linker group (L) comprises a chemical structural unit represented bythe formula: -A_(q)-, in which q is an integer greater than 1; and A isindependently selected from the group consisting of a bond,CR^(L1)R^(L1), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3),NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁ cycloalkyl optionallysubstituted with 0-6 R^(L1) and/or R^(L2) groups, and heteroaryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, whereinR^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are each independentlyselected from the group consisting of H, halo, C₁₋₈ alkyl, OC₁₋₈ alkyl,SC₁₋₈ alkyl, NHC₁₋₈ alkyl, N(C₁₋₈ alkyl)₂, C₃₋₁₁ cycloalkyl, aryl,heteroaryl, C₃₋₁₁ heterocyclyl, OC₁₋₈ cycloalkyl, SC₁₋₈ cycloalkyl,NHC₁₋₈ cycloalkyl, N(C₁₋₈cycloalkyl)2, N(C₁₋₈ cycloalkyl)(C₁₋₈ alkyl),OH, NH₂, SH, SO₂C₁₋₈ alkyl, P(O)(OC₁₋₈ alkyl)(C₁₋₈ alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈ alkyl, CCH, CH═CH(C₁₋₈ alkyl), C(C₁₋₈ alkyl)═CH(C₁₋₈alkyl), C(C₁₋₈ alkyl)═C(C₁₋₈ alkyl)₂, Si(OH)₃, SiC(₁₋₈ alkyl)₃,Si(OH)(C₁₋₈ alkyl)₂, COC₁₋₈ alkyl, CO₂H, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅,SO₂NHC₁₋₈ alkyl, SO₂NHC₁₋₈ alkyl, SO₂N(C₁₋₈ alkyl)₂, SONHC₁₋₈ alkyl,SON(C₁₋₈ alkyl)₂, CONHC₁₋₈ alkyl, CON(C₁₋₈ alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)CON(C₁₋₈ alkyl)₂, NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈ alkyl)₂, NHCONH₂, N(C₁₋₈ alkyl)SO₂NH(C₁₋₈ alkyl),N(C₁₋₈ alkyl)SO₂N(C₁₋₈ alkyl)₂, NHSO₂NH(C₁₋₈ alkyl), NHSO₂N(C₁₋₈ alkyl)₂and NHSO₂NH₂. R^(L1) and R^(L2) each, independently can be linked toanother A group to form a cycloalkyl and or heterocyclyl moiety that canbe further substituted with 0-4 R^(L5) groups.

In certain embodiments, the E3LB moiety may be selected from a varietyof moieties, including the following structures:

wherein “

” in the above structures, represents a bond that may be stereospecific

((R) or (S)), or non-stereospecific;

-   -   R¹ is described above;    -   R⁴ consists of H, alkyl (linear, branched, optionally        substituted with R⁵), OH, R⁵OCOOR⁶, R⁵OCONR⁵R⁷, CH₂-heterocyclyl        optionally substituted with R⁵, or benzyl optionally substituted        with R⁵;    -   R⁵ and R⁷ are each independently a bond, H, alkyl (linear,        branched), cycloalkyl, aryl, hetaryl heterocyclyl, or —C(═O)R⁶        each of which is optionally substitute; and

R⁶ includes CONR⁵R⁷, OR⁵, NR⁵R⁷, SR⁵, SO₂R⁵, SO₂NR⁵R⁷, CR⁵R⁷, CR⁵NR⁵R⁷,aryl, hetaryl, alkyl (linear, branched, optionally substituted),cycloalkyl, heterocyclyl, P(O)(OR⁵)R⁷, P(O)R⁵R⁷, OP(O)(OR⁵)R⁷,OP(O)R⁵R⁷, Cl, F, Br, I, CF₃, CHF₂, CH₂F, CN, NR⁵SO₂NR⁵R⁷, NR⁵CONR⁵R⁷,CONR⁵COR⁷, NR⁵C(═N—CN)NR⁵R⁷, C(═N—CN)NR⁵R⁷, NR⁵C(—N═CN)R⁷,NR⁵C(═C—NO₂)NR⁵R⁷, SO₂NR⁵COR⁷, NO₂, CO—R⁵, C(C═N—OR⁵)R⁷, CR⁵, CR⁵R⁷,CCR⁵, S(C═O)(C═N—R⁵)R⁷, SF₅, R⁵NR⁵R⁷, (RO)_(n)R⁷, or OCF₃, where n is aninteger from 1 to 10.

The E3LB moiety may also be selected from E3LB-e and E3LB-f as describedbelow:

wherein L is the linker previously described; R⁸ is H, a straight chainor branched C₁₋₈ alkyl, C₃₋₆ cycloalkyl, halo, CFH₂, CF₂H, or CF₃; andR⁹ is a H, halo, 4-methylthiazol-5-ylm, or oxazol-5-yl.

wherein L is the linker previously described and R¹¹ are independentlyoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substitutedheterocyclyalkyl wherein the substituents are alkyl, halogen, or OH.

The E3LB moiety may also be selected from E3LB-g, E3LB-h, E3LB-i,E3LB-j, and E3LB-k as described below:

wherein L is the linker previously described;

R¹⁰ are independently optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted arylalkyl, optionally substituted aryl,optionally substituted thioalkyl wherein the substituents attached tothe S atom of the thioalkyl are optionally substituted alkyl, optionallysubstituted branched alkyl, optionally substituted heterocyclyl,(CH₂)_(v)COR¹⁴, CH₂CHR¹⁵COR¹⁶ or CH₂R¹⁷, where v=1 to 3; R¹⁴ and R¹⁶ areindependently selected from OH, NR¹⁸R¹⁹, or —OR²⁰; R¹⁵ is —NR¹⁸R¹⁹. R¹⁷is optionally substituted aryl or optionally substituted heterocyclyl,where the optional substituents include alkyl and halogen; R¹⁸ ishydrogen or optionally substituted alkyl; R¹⁹ is hydrogen, optionallysubstituted alkyl, optionally substituted branched alkyl, optionallysubstituted arylalkyl, optionally substituted heterocyclyl,—CH₂(OCH₂CH₂O)_(w)CH₃, or a polyamine chain, where w=1 to 8; andoptional substituents may be OH, halo, or NH₂;

R¹² and R¹³ are independently hydrogen, optionally substituted alkyl, oroptionally substituted cycloalkyl;

X is CH2, N, or O; Y is S or O;

D is a bond (direct bond between X and L) or a ring which may be aryl,heteroaryl independently substituted by 1 or more halo, hydroxyl, nitro,CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1 or morehalo), CF₃, C₁ alkyl (linear, branched, optionally substituted by 1 ormore halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionallysubstituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-6 memberedalicyclic with 0-4 heteroatoms and substituted by 1 or more halo,hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆ alkyl (linear, branched, optionallysubstituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy (linear,branched, optionally substituted by 1 or more halo), C₂₋₆ alkenyl, orC₂₋₆ alkynyl. R², R³ is independently H, halo, C₁₋₆ alkyl (optionallysubstituted by 1 or more F) or taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms;and

R²⁰ is selected from the group consisting of:

wherein A is a C₄₋₈ aliphatic ring, and B is an aryl or N-containingheteroaryl and optionally substituted by alkyl or haloalkyl.

Optionally, E3LB may be selected from the MDM2 class of E3 ligasesrepresented by E3LB-1 below.

wherein R²² is independently aryl or heteroaryl optionally substitutedby halogen, mono-, di or tri-substituted halogen;

R²¹ is independently aryl or heteroaryl, optionally substituted bymono-, di- or tri-substituted halogen, CN, ethynyl, cyclopropyl, methyl,ethyl, isopropyl, methoxy, ethoxy, isopropoxy, other C₁₋₆ alkyl, otherC₁₋₆ alkenyl and C₁₋₆ alkynyl;

R²³ is selected from alkyl, substituted alkyl, alkenyl, substitutedalkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl andsubstituted cycloalkenyl;

R²⁴ is H, alkyl, aryl, substituted alkyl, cycloalkyl, aryl substitutedcycloakyl and alkoxy substituted cycloalkyl; and

E is para-substituted aryl, single or multiple N containing heteroaryloptionally substituted by —OCH₃, —OCH₂CH₃ and Halogen. L is the linkerpreviously defined above.

The E3LB moiety is inclusive of all cereblon binders such asimmunomodulatory imide drugs (IMiDs) including thalidomide,pomalidomide, and lenalidomide, and analogs or derivatives thereof, aswell as E3 CRL2^(VHL) compounds, the cellular inhibitor of apoptosisprotein (IAP), and the mouse double minute 2 (MDM2) binders.

In certain embodiments, the compounds as described herein comprise aplurality of E3LB moieties and/or a plurality of ARB moieties. Incertain additional embodiments, the compounds as described hereincomprise multiple ARB moieties (targeting the same or differentlocations of the AR), multiple E3LB moieties, one or more moieties thatbind specifically to another E3 ubiquitin ligase, e.g., VHL, IAP, MDM2,or a combination thereof. In any of the aspects of embodiments describedherein, the ARB moieties, E3LB moieties, and other moieties that bindspecifically to another E3 ubiquitin ligase can be coupled directly orvia one or more chemical linkers or a combination thereof. In additionalembodiments, where a compound has multiple moieties that bindspecifically to another E3 ubiquitin ligase, the moieties can be for thesame E3 ubiquitin ligase or each respective moiety can bind specificallyto a different E3 ubiquitin ligase. In those embodiments where acompound has multiple ARB moieties, such moieties may be the same or,optionally, different.

In certain embodiments, where the compound comprises multiple E3LBmoieties, the E3LB moieties are identical or, optionally, different. Inadditional embodiments, the compound comprising a plurality of E3LBmoieties further comprises at least one ARB moiety coupled to a E3LBmoiety directly or via a chemical linker (“L”) or both. In certainadditional embodiments, the compound comprising a plurality of E3LBmoieties further comprises multiple ARB moieties. In still additionalembodiments, the ARB moieties are the same or, optionally, different.

In certain embodiments, the compound is selected from the groupconsisting of the exemplary compounds as described below, and salts andpolymorphs thereof:

Example 1

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide Example 2

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(8-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide Example 3

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(10-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisondolin-4-yl)amino)decyl)acetamide Example 4

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide Example 5

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide Example 6

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)acetamide Example 7

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetamido)hexyl)acetamide Example 8

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetamido)octyl)acetamide Example 9

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(10-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)acetamide Example 10

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl)aceta- mide Example 11

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)acetamide Example 12

4-((2-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione Example 13

4-((2-(2-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione Example 14

N-(14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamideExample 15

(2S,4R)-1-((S)-2-(4-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide Example 16

(2S,4R)-1-((S)-2-(5-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide Example 17

(2S,4R)-1-((S)-2-(6-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide Example 18

(2S,4R)-1-((S)-2-(7-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide Example 19

(2S,4R)-1-((S)-2-(2-(3-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 20

(2S,4R)-1-((S)-2-(tert-butyl)-14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-4,13-dioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 21

(2S,4R)-1-((S)-2-(8-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide Example 22

(2S,4R)-N-((S)-3-((4-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide Example 23

(2S,4R)-N-((S)-3-((6-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide Example 24

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)-1- ((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2- carboxamide Example 25

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl-N-((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2- carboxamide Example 26

(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2- carboxamide Example 27

(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2- carboxamide Example 28

(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2- carboxamide Example 29

(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2- carboxamide Example 30

N-(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)-2-morpholinobenzo[d]thiazole-4- carboxamide Example 31

N-(6-((S)-2-((S)-1-((S)-2-cyclohexyl-2-((S)- 2-(methylamino)propanamido)acetyl)pyrrolidine- 2-carboxamido)-3,3-diphenylpropanamido)hexyl)-2- morpholinobenzo[d]thiazole-4-carboxamideExample 32

N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4- carboxamide Example 33

2,5-dibromo-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4- carboxamide Example 34

4-((10-aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

In one aspect, the disclosure provides compounds of formula (I):

which is referred to as Androgen Receptor Binder-Linker-E3 Ligase Binder(I)

EXAMPLES

Unless otherwise noted, starting materials, reagents, and solvents wereobtained from commercial suppliers (e.g. Acros Organics, Sigma-Aldrich,Alfa Aesar, Fluorochem, and Merck) and were used without furtherpurification. Reactions were routinely monitored by thin-layerchromatography (TLC) performed on silica gel 60 F₂₅₄ (layer 0.2 mm)pre-coated aluminium foil (with fluorescent indicatorUV254)(Sigma-Aldrich). Developed plates were air-dried and visualizedunder UV light (254/365 nm) or by using KMnO₄ or ninhydrin solutions.Flash column chromatography was performed on Merck silica gel 60 (mesh230-400).

¹H NMR and ¹³C NMR spectra were recorded at room temperature at 400 and101 MHz, respectively, on a Bruker Avance 400 spectrometer by using TMSor residual solvent peak as internal standard. Chemical shifts arereported in ppm (δ) and the coupling constants (J) are given in Hertz(Hz). Peak multiplicities are abbreviated as follow: s (singlet), bs(broad singlet), d (doublet), dd (double doublet), t (triplet), dt(double triplet), q (quartet), p (pentet), and m (multiplet).

High-Resolution Mass Spectroscopy (HRMS) spectra were registered onAgilent Technologies 6540 UHD Accurate Mass Q-TOF LC-MS system. Thepurity of all final compounds that were evaluated in biological assayswas assessed as >95%, using LC-MS. The analyses were carried outaccording to the method listed below. The mobile phase was a mixture ofwater (solvent A) and acetonitrile (solvent B), both containing formicacid at 0.1%. Method: Acquity UPLC BEH C18 1.7 μm (C18, 150×2.1 mm)column at 40° C. using a flow rate of 0.65 mL/min in a 10 min gradientelution. Gradient elution was as follows: 99.5:0.5 (A/B) to 5:95 (A/B)over 8 min, 5:95 (A/B) for 2 min, and then reversion back to 99.5:0.5(A/B) over 0.1 min. The UV detection is an averaged signal fromwavelength of 190 nm to 640 nm and mass spectra are recorded on a massspectrometer using positive mode electro spray ionization. The chemicalnames were generated using ChemBioDraw 12.0 from CambridgeSoft.

Compounds described herein may be synthesized as described herein, usingmodified methods described herein or by methods known to a person ofskill in the art.

Chemistry Abbreviations:

ACN, acetonitrile; AcOH, acetic acid; AcOK, potassium acetate; Boc,tert-butoxycarbonyl; CD₃OD, deuterated methanol; CDCl₃, deuteratedchloroform; DCE, dichloroethane; DCM, dichloromethane; DEE, diethylether; DIAD, diisopropyl azodicarboxylate; DIPEA,N,N′-diisopropylethylamine; DMA, dimethylacetamide; DMF,dimethylformamide; DMSO, dimethylsulfoxide; DMSO-d₆, deuterateddimethylsulfoxide; EA, ethyl acetate; h, hour, EDC,1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et₃N, triethylamine;HATU, 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; min, minutes; HOBt, 1-hydroxybenzotriazole; HRMS,high-resolution mass spectroscopy; MeOH, methanol; NMR, nuclear magneticresonance; tBu, tert-butyl; THF, tetrahydrofuran; TLC, thin-layerchromatography, TMS, tetramethylsilane; PE, petroleum ether; rt, roomtemperature.

Chemical Synthesis

Compounds of general formula (I) may be prepared by the generalsynthetic approaches described below (General Scheme 1 and 2), togetherwith synthetic methods known in the art of organic chemistry. In allmethods, it is well-understood that protecting groups for sensitive orreactive groups may be employed where necessary in accordance withgeneral principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Green and P.G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3′ edition,John Wiley & Sons). These groups are removed at a convenient stage ofthe compound synthesis using methods that are readily apparent to thoseskilled in the art. The selection of processes as well as the reactionconditions and order of their execution shall be consistent with thepreparation of compounds of Formula (I).

ARB: Androgen Receptor (AR) Binder; E3LB: E3 Ligase Binder.

2,3-Difluorophenyl acetate (A)

The titled compound can be prepared according to the process describedby Huifang Li et al. J. Med. Chem. 2014, 57, 6458-6467. Acetyl chloride(commercially available from, for example, Fluorochem) (6.01 mL, 6.63 g,84.55 mmol) was slowly added at rt to a stirred solution of2,3-difluorophenol (commercially available from, for example,Fluorochem) (10.0 g, 76.87 mmol) and pyridine (6.83 mL, 6.68 g, 84.55mmol) in dry DCM (60.0 mL). After 2 h, the mixture was diluted with 2NHCl (60 mL) and the aqueous layer was separated and extracted with DCM(30 mL×3). The reunited organic phases were washed with brine (20 mL×2),dried over anhydrous Na₂SO₄, and concentrated under reduced pressure toafford the titled compound (13.26 g, 99% yield) as a colorless oil. ¹HNMR (400 MHz, CDCl₃): δ 7.16-7.03 (m, 2H), 6.99-6.83 (m, 1H), 2.37 (s,3H); ¹³C NMR (101 MHz, CDCl₃): δ 167.96, 151.26 (dd, J=10.9, 249.4 Hz),143.29 (dd, J=14.3, 251.5 Hz), 139.55 (dd, J=2.3, 10.1 Hz), 123.36 (dd,J=5.0, 7.9 Hz), 118.78 (d, J=3.5 Hz), 114.71 (d, J=17.3 Hz), 20.44.

1-(3,4-Difluoro-2-hydroxyphenyl)ethan-1-one (B)

The titled compound can be prepared according to the process describedby Gomtsyan, Arthur R. et al. PCT Int. Appl. WO2010045401. AlCl₃ (1.55g, 11.62 mmol) was added under nitrogen at 0° C. in small portions to astirred solution of 2,3-difluorophenyl acetate (A) (2.00 g, 11.62 mmol)in DCE (3.0 mL). After addition was completed, the mixture was refluxedfor 14 h. After cooling at rt, the solvent was evaporated and theresidue diluted with DCM (20 mL). 2N HCl (10 mL) was added, and themixture was stirred for 20 min. Organic phase was separated, the waterextracted with DCM (10 mL×2), and the reunited organic phases were driedover anhydrous Na₂SO₄ and concentered under reduced pressure to give thetitled compound (1.95 g, 97% yield) as a brownish solid. ¹H NMR (400MHz, CDCl₃): δ 12.59 (d, J=1.4 Hz, 1H), 7.55 (ddd, J=2.3, 5.5, 9.1 Hz,1H), 6.86-6.63 (m, 1H), 2.65 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ203.66, 157.02, 154.88 (dd, J=9.7, 257.9 Hz), 139.98 (dd, J=13.7, 249.7Hz), 125.92 (dd, J=4.5, 10.0 Hz), 117.77, 107.24 (d, J=18.7 Hz), 26.78.

2-Bromo-1-(3,4-difluoro-2-hydroxyphenyl)ethan-1-one (C)

The titled compound can be prepared according to the process describedby Huifang Li et al. J. Med. Chem. 2014, 57, 6458-6467. A solution of1-(3,4-difluoro-2-hydoxyphenyl)ethan-1-one (B) (1.95 g, 11.33 mmol) inEA (40.0 mL) was added dropwise at rt to a stirred suspension of CuBr₂(3.03 g, 13.59 mmol) in EA (40 mL). After 24 h of reflux, the mixturewas allowed to cool at rt, filtered over Celite, and the filtrateevaporated to dryness. The crude residue was purified by flash columnchromatography on SiO₂ (PE/EA, 95:5) to give the titled compound (1.55g, 69% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 12.10-11.84(m, 1H), 7.58 (ddd, J=2.2, 5.4, 8.9 Hz, 1H), 6.93-6.65 (m, 1H), 2.65 (s,2H); ¹³C NMR (101 MHz, CDCl₃): δ 196.41, 155.36 (dd, J=9.7, 259.7 Hz),154.11 (dd, J=5.6, 9.6 Hz), 140.29 (dd, J=13.9, 251.0 Hz), 125.92 (dd,J=4.6, 10.1 Hz), 115.13, 107.90 (d, J=19.1 Hz), 29.31.

2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenol (ARB-1)

The titled compound can be prepared according to the process describedby Huifang Li et al. J. Med. Chem. 2014, 57, 6458-6467.Morpholine-4-carbothioamide (commercially available from, for example,Fluorochem)(0.330 g, 2.26 mmol) was added in small portions to a stirredsolution of compound 2-bromo-1-(3,4-difluoro-2-hydroxyphenyl)ethan-1-one(C) (0.568 g, 2.26 mmol) in absolute EtOH (10 mL) at 0° C. When additionwas completed, the mixture was refluxed for 4 h. After cooling at rt,the mixture was evaporated to dryness and NaHCO₃ saturated solution (20mL) was added to pH 8. The aqueous phase was extracted with EA (10mL×3), the reunited organic phases were dried over anhydrous Na₂SO₄ andconcentered under reduced pressure to give a solid which was trituredwith DEE and filtered affording the titled compound (0.590 g, 87% yield)as a light-yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 12.43 (s, 1H), 7.24(ddd, J=2.3, 5.6, 8.5 Hz, 1H), 6.76 (s, 1H), 6.66 (td, J=7.2, 9.3 Hz,1H), 4.00-3.84 (m, 4H), 3.63-3.43 (m, 4H); ¹³C NMR (101 MHz, CDCl₃): δ171.13, 151.23 (dd, J=10.4, 247.9 Hz), 148.09, 147.25-146.05 (m), 140.72(dd, J=14.2, 244.7 Hz), 119.63 (dd, J=4.5, 8.7 Hz), 115.71, 106.97 (d,J=18.4 Hz), 100.25 (d, J=1.7 Hz), 65.90 (2C), 48.31 (2C).

Tert-butyl 2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetate(D)

Tert-butyl bromoacetate (commercially available from, for example,Sigma-Aldrich) (0.434 mL, 0.575 g, 2.95 mmol) was added to a stirredsuspension of 2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol (ARB-1)(0.800 g, 2.68 mmol) and K₂CO₃ (0.927 g, 6.71 mmol). The suspension wasstirred for 18 h at rt, filtered, and the filtrate evaporated todryness. Residue was purified by flash column chromatography on SiO₂(PE/EA, 95:5 to 90:10) to afford the titled compound (0.800 g, 73%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.92 (ddd, J=2.3,6.2, 8.8 Hz, 1H), 7.68 (s, 1H), 7.10-6.87 (m, 1H), 4.67 (d, J=1.7 Hz,2H), 4.00-3.79 (m, 4H), 3.68-3.47 (m, 4H), 1.53 (s, 9H); ¹³C NMR (101MHz, CDCl₃): δ 169.77, 167.40, 150.32 (dd, J=11.8, 249.8 Hz), 145.30,144.64-144.23 (m), 143.98 (dd, J=14.4, 246.1 Hz), 124.35, 124.04 (dd,J=3.9, 7.8 Hz), 111.42 (d, J=17.0 Hz), 107.71, 82.55, 70.00 (d, J=7.5Hz), 66.22 (2C), 48.61 (2C), 28.09 (3C).

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic Acid (E)

A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetate (D)(0.780 g,1.89 mmol) and the resulting suspension was stirred at rt for 16 h. Thesolvent was evaporated to dryness and the residue was tritured with DEE.The solids were collected by filtration and dried under vacuo to affordthe titled compound (0.672 g, 91% yield) as light-yellow solid. ¹H NMR(400 MHz, CD₃OD): δ 7.48 (ddd, J=2.3, 5.7, 8.1 Hz, 1H), 7.27 (s, 1H),7.18 (td, J=7.5, 9.2 Hz, 1H), 5.01 (d, J=1.5 Hz, 2H), 4.02-3.86 (m, 4H),3.86-3.67 (m, 4H); ¹³C NMR (101 MHz, CD₃OD): δ 171.72, 169.44, 152.57(dd, J=11.6, 252.2 Hz), 144.55 (d, J=1.7 Hz), 143.30 (dd, J=15.0, 248.0Hz), 136.41 (d, J=13.3 Hz), 124.82 (dd, J=3.9, 8.6 Hz), 118.47, 111.66(d, J=18.2 Hz), 106.15, 69.24 (d, J=9.0 Hz), 65.05 (2C), 49.17 (2C).

2-(2,6-Dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)

The titled compound can be prepared according to the process describedby Bradner James et al. PCT Int. Appl., WO2016/105518. A mixture of3-fluorophthalic anhydride (commercially available from, for example,Fluorochem)(1.00 g, 6.02 mmol), 3-aminopiperidine-2,6-dionehydrochloride (commercially available from, for example, Fluorochem)(1.09 g, 6.62 mmol), and potassium acetate (1.83 g, 18.66 mmol) in AcOH(20 mL) was stirred at 90° C. overnight. After cooling to rt, the blackreaction mixture was poured in ice-water yielding a brown solid whichwas filtered and purified by flash column chromatography on SiO₂ (PE/EA,4:6) to afford the titled compound as a white solid (1.22 g, 73% yield).¹H NMR (400 MHz, DMSO-d₆): δ 11.16 (s, 1H), 8.03-7.89 (m, 1H), 7.80 (d,J=7.3 Hz, 1H), 7.74 (t, J=8.9 Hz, 1H), 5.17 (dd, J=12.8, 5.4 Hz, 1H),3.00-2.81 (m, 1H), 2.71-2.53 (m, 2H), 2.13-1.99 (m, 1H); ¹³C NMR (101MHz, DMSO-d₆): δ 173.19, 170.14, 166.55 (d, J=2.9 Hz), 164.42, 157.25(d, J=262.3 Hz), 138.51 (d, J=7.9 Hz), 133.90 (d, J=1.3 Hz), 123.46 (d,J=19.6 Hz), 120.50 (d, J=3.3 Hz), 117.48 (d, J=12.6 Hz), 49.54, 31.36,22.30.

General Procedure I: Nucleophilic Substitution on FluorothalidomideTert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamate(F)

The titled compound can be prepared according to the process describedby Ishoey, M. et al. ACS Chem. Biol., 2018, 13, 553-560. Under nitrogenatmosphere, a mixture of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.050g, 0.181 mmol, 1.0 equiv), tert-butyl (6-aminohexyl)carbamate(commercially available from, for example, Fluorochem) (0.043 g, 0.199mmol, 1.1 equiv), and DIPEA (0.061 mL, 0.362 mmol, 2.0 equiv) in dry THF(2.0 mL) was reacted at 70° C. for 4 h (in this case, the reaction wasperformed in a pressure tube). After cooling to rt, the solvent wasevaporated to dryness and the crude residue was purified by flash columnchromatography on SiO₂ (DCM/Acetone, 8:2) to give a fluorescent yellowsolid (0.040 g, 47% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.35 (bs, 1H),7.50 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H),6.25 (bs, 1H), 4.95 (dd, J=8.0 and 16 Hz, 1H), 4.55 (bs, 1H), 3.25 (t,J=8.0 Hz, 2H), 3.15-3.10 (m, 2H), 2.95-2.70 (m, 3H), 2.20-2.10 (m, 1H),1.70-1.60 (m, 2H), 1.55-1.35 (m, 15H); ¹³C NMR (101 MHz, CDCl₃): δ171.16, 169.52, 168.45, 167.64, 156.02, 146.97, 136.13, 132.49, 116.64,111.41, 109.87, 79.15, 42.55, 40.45, 31.42, 30.02, 29.15, 28.43 (3C),26.62, 26.47, 22.81.

Tert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate(G)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.General Procedure I (2 h) was followed by using2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1) (0.15g, 0.543 mmol), tert-butyl (8-aminooctyl)carbamate (0.146 g, 0.597mmol), and DIPEA (0.18 mL, 1.086 mmol) in NMP (5.0 mL) to afford thetitled compound as fluorescent yellow solid (0.103 g, 39% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH98:2). ¹H NMR (400 MHz, CDCl₃): 8.05 (bs, 1H), 7.52 (dd, J=8.4 Hz, 1H),7.11 (d, J=7.1 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.25 (bs, 1H), 4.94 (dd,J=12.1 and 5.3 Hz, 1H), 4.55 (bs, 1H), 3.28 (t, J=6.9 Hz, 2H), 3.19-3.01(m, 2H), 2.99-2.66 (m, 3H), 2.20-2.12 (m, 1H), 1.78-1.54 (m, 6H),1.53-1.40 (m, 14H), 1.38-1.31 (m, 1H).

Tert-butyl(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)carbamate(H)

General Procedure I (10 h) was followed by using2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1) (0.20g, 0.724 mmol), tert-butyl (10-aminodecyl)carbamate (0.217 g, 0.796mmol), and DIPEA (0.25 mL, 1.448 mmol) in dry DMF (4.0 mL) to afford thetitled compound as fluorescent yellow film (0.122 g, 34% yield)following purification by flash column chromatography on SiO₂(DCM/Acetone 9:1). ¹H NMR (400 MHz, CDCl₃): δ 8.36 (bs, 1H), 7.50 (dd,J=8.3, 7.3 Hz, 1H), 7.09 (d, J=7.1 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.25(t, J=5.5 Hz, 1H), 4.93 (dd, J=12.0, 5.4 Hz, 1H), 4.56 (s, 1H), 3.27(dd, J=12.8, 6.9 Hz, 2H), 3.16-3.03 (m, 2H), 2.94-2.68 (m, 3H),2.17-2.07 (m, 1H), 1.72-1.59 (m, 2H), 1.52-1.38 (m, 11H), 1.36-1.24 (m,12H); ¹³C NMR (101 MHz, CDCl₃): δ 171.17, 169.52, 168.46, 167.66,155.99, 147.03, 136.10, 132.50, 116.65, 111.33, 109.80, 79.04, 48.86,42.65, 40.62, 31.42, 30.05, 29.39 (2C), 29.23 (2C), 28.44 (3C), 26.89,26.77, 22.81 (2C).

Tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate(I)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.General Procedure I (2 h) was followed by using2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.150g, 0.597 mmol), tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate(0.134 g, mmol), and DIPEA (0.18 mL, 0.108 mmol) in NMP (2.0 mL) toafford the titled compound as fluorescent yellow film (0.040 g, 14%yield) following double purification by flash column chromatography onSiO₂ (first: DCM/MeOH 98:2; second: PE/EA 6:4). ¹H NMR (400 MHz, CDCl₃):8.33 (s, 1H), 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.13 (d, J=7.0 Hz, 1H), 6.94(d, J=8.5 Hz, 1H), 5.09 (s, 1H), 4.96 (s, 1H), 3.75 (t, J=5.3 Hz, 2H),3.72-3.63 (m, 4H), 3.59 (t, J=5.2 Hz, 2H), 3.50 (t, J=5.2 Hz, 2H),3.37-3.30 (m, 2H), 2.93-2.70 (m, 3H), 2.18-2.11 (m, J=9.2, 4.2 Hz, 1H),1.45 (s, 9H); 13C NMR (101 MHz, CDCl₃): δ 170.97, 169.31, 168.32,167.59, 156.08, 146.80, 136.06, 132.55, 116.71, 111.71, 110.41, 79.31,70.80, 70.38, 70.15, 69.36, 48.89, 42.33, 40.41, 31.40, 28.42 (3C),22.88.

Tert-butyl(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate(J)

The titled compound can be prepared according to the process describedby Peng, L. et al. ACS Med. Chem. Lett. 2019, 10, 767-772. GeneralProcedure I (4 h) was followed by using2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.250 g, 0.905 mmol), tert-butyl(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (0.291 g, 0.995mmol), and DIPEA (0.31 mL, 1.810 mmol) in dry DMF (4.0 mL) to afford thetitled compound as fluorescent yellow film (0.085 g, 15% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH98:2). ¹H NMR (400 MHz, CDCl₃): δ 8.61 (s, 1H), 7.52-7.43 (m, 1H),7.15-7.06 (m, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.52-6.46 (m, 1H), 5.08 (s,1H), 4.93 (dd, J=11.8 and 5.4 Hz, 1H), 3.73 (t, J=5.2 Hz, 2H), 3.70-3.59(m, J=18.3, 4.8 Hz, 8H), 3.58-3.51 (m, 2H), 3.51-3.42 (m, 2H), 3.37-3.23(m, 2H), 2.93-2.65 (m, 3H), 2.15-2.07 (m, 1H), 1.44 (s, 9H); ¹³C NMR(101 MHz, CDCl₃): δ 171.38, 169.29, 168.56, 167.64, 156.05, 146.82,136.03, 132.51, 116.78, 111.64, 110.29, 79.22, 70.73, 70.60, 70.59,70.21, 70.18, 69.50, 48.87, 42.37, 40.34, 31.43, 28.42 (3C), 22.78.

Tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate(K)

General Procedure I (10 h) was followed by using2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.225 g, 0.814 mmol), tert-butyl(14-amino-3,6,9,12-tetraoxatetradec-1-yl)carbamate (0.301 g, 0.896mmol), and DIPEA (0.28 mL, 1.629 mmol) in dry DMF (4.0 mL) to afford thetitled compound as yellow film (0.060 g, 13% yield) followingpurification by flash column chromatography on SiO₂ (DCM/MeOH 98:5). ¹HNMR (400 MHz, CDCl₃): δ 8.27 (bs, 1H), 7.58-7.42 (m, 1H), 7.13 (d, J=7.1Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.52 (bs, 1H), 5.11 (bs, 1H), 4.93 (dd,J=5.3, 12.0 Hz, 1H), 3.85-3.43 (m, 18H), 3.32 (s, 2H), 2.89-2.63 (m,3H), 2.26-2.06 (m, 1H), 1.46 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ171.00, 169.24, 168.30, 167.59, 156.03, 146.85, 136.05, 132.52, 116.78,111.67, 110.31, 79.19, 70.79, 70.66, 70.59 (4C), 70.45, 70.28, 69.47,48.86, 42.40, 31.42, 28.44 (3C), 22.83.

General Procedure II: Amine Boc-Deprotection4-((6-Aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (L)

A solution of 4N HCl in dioxane (2.0 mL) was added to tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamate(F) (0.10 g, 0.212 mmol, 1.0 equiv) and the resulting solution wasstirred at rt for 16 h. The solvent was evaporated to dryness and theresidue was tritured with DEE, collected by filtration, and dried undervacuo to afford the titled compound as yellow solid (0.084 g, 97%yield), which was used in the successive step without furtherpurification. ¹H NMR (400 MHz, CD₃OD): δ 7.61-7.49 (m, 1H), 7.13-7.01(m, 2H), 5.08 (dd, J=5.4, 12.3 Hz, 1H), 3.38 (t, J=7.0 Hz, 2H),3.00-2.90 (m, 2H), 2.90-2.68 (m, 3H), 2.18-2.05 (m, 1H), 1.87-1.65 (m,4H), 1.65-1.38 (m, 4H).

4-((8-Aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (M)

General Procedure II (16 h) was followed by using tert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate(G) (0.095 g, 0.189 mmol) and 4N HCl in dioxane (1.7 mL) to afford thetitled compound as yellow solid (0.080 g, 96% yield). ¹H NMR (400 MHz,MeOD): δ 7.62-7.46 (m, 1H), 7.14-6.92 (m, 2H), 5.08 (dd, J=5.5, 12.5 Hz,1H), 3.36 (t, J=6.9 Hz, 2H), 2.99-2.90 (m, 2H), 2.90-2.66 (m, 3H),2.17-2.09 (m, 1H), 1.81-1.61 (m, 4H), 1.61-1.40 (m, 8H).

4-((10-Aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (N)(Example 34)

General Procedure II (16 h) was followed by using tert-butyl(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)carbamate(H) (0.079 g, 0.149 mmol) and 4N HCl in dioxane (1.0 mL) to afford thetitled compound as yellow solid (0.052 g, 75% yield). ¹H NMR (400 MHz,MeOD): δ 7.57 (dd, J=8.3, 7.4 Hz, 1H), 7.09-7.03 (m, 2H), 5.08 (dd,J=12.7, 5.4 Hz, 1H), 2.96-2.67 (m, 1H), 2.19-2.07 (m, 1H), 1.74-1.61 (m,4H), 1.51-1.35 (m, 14H). HRMS (ESI) m/z [M+H]+ calcd for C₂₃H₃₂N₄O₄429.24963. found 4292497.

4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (O)

General Procedure II (16 h) was followed by using tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate(1) (0.040 g, 0.079 mmol) and 4N HCl in dioxane (0.5 mL) to afford thetitled compound as yellow solid (0.022 g, 83% yield). ¹H NMR (400 MHz,MeOD): δ 7.59 (dd, J=8.6, 7.1 Hz, 1H), 7.11 (dd, J=10.6, 7.8 Hz, 2H),5.08 (dd, J=12.6, 5.5 Hz, 1H), 3.80-3.66 (m, 8H), 3.55 (t, J=5.1 Hz,2H), 3.18-3.08 (m, 2H), 2.95-2.64 (m, 3H), 2.22-2.08 (m, 1H).

4-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (P)

General Procedure II (16 h) was followed by using tert-butyl(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate(J) (0.075 g, 0.137 mmol) and 4N HCl in dioxane (0.8 mL) to afford thetitled compound as yellow solid (0.055 g, 83% yield). ¹H NMR (400 MHz,MeOD): δ 7.59 (dd, J=8.6 and 7.1 Hz, 1H), 7.11 (dd, J=12.5 and 7.9 Hz,2H), 5.08 (dd, J=12.4 and 5.5 Hz, 1H), 3.80-3.63 (m, 12H), 3.54 (t,J=5.2 Hz, 2H), 3.21-3.07 (m, 3H), 2.97-2.65 (m, 3H), 2.19-2.08 (m, 1H).

4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (Q)

General Procedure II (3 h) was followed by using tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate(K) (0.060 g, 0.101 mmol) and 4N HCl in dioxane (1.0 mL) to afford thetitled compound as yellow solid (0.050 g, 94% yield). ¹H NMR (400 MHz,MeOD): δ 7.58 (t, J=7.7 Hz, 1H), 7.30-6.86 (m, 2H), 5.08 (dd, J=5.5,12.3 Hz, 1H), 3.86-3.58 (m, 16H), 3.58-3.41 (m, 2H), 3.19-3.05 (m, 2H),2.88-2.64 (m, 3H), 2.21-1.98 (m, 1H).

General Procedure III: HATU-Mediated Amidation Reaction2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide(Example 1)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.048 g, 0.122 mmol, 1.0 equiv),4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (L) (0.050 g, 0.122 mmol, 1.0 equiv), and DIPEA (0.083 mL,0.489 mmol, 4.0 equiv) in dry DMF (3.0 mL) was added HATU (0.058 g,0.153 mmol, 1.25 equiv). Stirring was continued at rt for 16 h. Thereaction mixture was diluted with water (30 mL) and extracted with EA(15 mL×3). The reunited organic layers were washed with water (20 mL×3),brine (20 mL×3), dried over anhydrous Na₂SO₄ and then concentrated underreduced pressure to give a crude residue, which was purified by flashcolumn chromatography on SiO₂ (DCM/Acetone/MeOH, 90:10:0 to 89:10:1)affording a yellow solid (0.015 g, 18% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.09 (s, 1H), 7.63-7.56 (m, 1H), 7.56-7.48 (m, 1H), 7.11 (d, J=7.0 Hz,1H), 7.05 (s, 1H), 7.04-6.96 (m, 1H), 6.93 (s, 1H), 6.90 (d, J=8.5 Hz,1H), 6.25 (s, 1H), 4.93 (dd, J=5.3, 11.9 Hz, 1H), 4.60 (s, 2H),3.89-3.78 (m, 4H), 3.64-3.51 (m, 4H), 3.36 (q, J=6.8 Hz, 2H), 3.33-3.26(m, 2H), 2.97-2.68 (m, 3H), 2.18-2.11 (m, 1H), 1.79-1.35 (m, 8H); ¹³CNMR (101 MHz, CDCl₃): δ 170.87, 170.74, 169.50, 168.25, 167.92, 167.59,150.76 (dd, J=11.6, 251.4 Hz), 146.96, 146.37-146.09 (m), 144.62 (dd,J=1.5, 9.1 Hz), 144.15 (dd, J=14.0, 247.3 Hz), 136.15, 132.48, 125.04,124.53 (dd, J=4.0, 7.8 Hz), 116.63, 112.43 (d, J=172 Hz), 111.46,109.90, 105.96, 72.42 (d, J=4.9 Hz), 66.11 (2C), 48.87, 48.62 (2C),42.52, 38.95, 31.41, 29.42, 29.13, 26.62, 26.55, 22.82. HRMS (ESI) m/z[M+H]+ calcd for C₃H₃₆F₂N₆O₇S 711.2407. found 711.2412.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide(Example 2)

General Procedure III was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.02g, 0.056 mmol),4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (M) (0.024 g, 0.056 mmol), DIPEA (0.03 mL, 0.224 mmol),and HATU (0.027 g, 0.70 mmol) in dry DMF (1.0 mL) to afford the titledcompound as yellow solid (0.016 g, 50% yield) following purification byflash column chromatography on SiO₂(DCM/MeOH, 99:1 to 96:4) followed byfurther HPLC purification (Agilent Technologies 1200; column, EclipseXDB-C18 4.6×150 mm (5 μm); flow rate, 1.0 mL/min; DAD 190-650 nm;isocratic eluent, ACN/H₂O 70:30). ¹H NMR (400 MHz, CDCl₃): δ 8.14 (s,1H), 7.64-7.55 (m, 1H), 7.55-7.45 (m, 1H), 7.11 (d, J=7.1 Hz, 1H), 7.04(s, 1H), 7.04-6.97 (m, 1H), 6.93 (s, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.25(s, 1H), 5.02-4.86 (m, 1H), 4.60 (s, 2H), 3.97-3.76 (m, 4H), 3.64-3.48(m, 4H), 3.34 (q, J=6.8 Hz, 2H), 3.28 (q, J=6.6 Hz, 2H), 2.99-2.67 (m,3H), 2.21-2.08 (m, 1H), 1.81-1.31 (i, 12H); ¹³C NMR (101 MHz, CDCl₃): δ170.90, 170.71, 169.50, 168.28, 167.88, 167.61, 150.78 (dd, J=10.5,249.5 Hz), 147.01, 146.45-145.86 (m), 144.63 (d, J=10.5 Hz), 144.14 (dd,J=14.0, 247.4 Hz), 136.12, 132.49, 124.99, 124.52 (dd, J=3.8, 7.8 Hz),116.65, 112.41 (d, J=17.2 Hz), 111.39, 109.86, 105.96, 72.41 (d, J=5.1Hz), 66.11 (2C), 48.86, 48.62 (2C), 42.59, 39.10, 31.42, 29.45, 29.14,29.12, 29.11, 26.78, 26.72, 22.84. HRMS (ESI) m/z [M+H]+ calcd forC₃₆H₄₀F₂N₆O₇S 739.27200. found 739.27369.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)acetamide(Example 3)

General Procedure III was followed by using2-(2,3-difluoro-4-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.04g, 0.086 mmol),4-((10-aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (N) (0.04 g, 0.086 mmol), DIPEA (0.05 mL, 0.44 mmol) andHATU (0.041 g, 0.107 mmol) in dry DMF (2.0 mL) to afford the titledcompound as yellow solid (0.026 g, 39% yield) following purification byflash column chromatography on SiO₂ (DCM/Acetone, 95:5 to 85:15). ¹H NMR(400 MHz, CDCl₃): δ 8.16 (s, 1H), 7.61 (ddd, J=8.4, 6.0, 2.1 Hz, 1H),7.55-7.47 (m, 1H), 7.10 (d, J=7.1 Hz, 1H), 7.06-6.95 (m, 2H), 6.94 (s,1H), 6.90 (d, J=8.5 Hz, 1H), 6.25 (t, J=5.6 Hz, 1H), 4.93 (dd, J=12.1,5.3 Hz, 1H), 4.59 (s, 2H), 3.93-3.78 (m, 4H), 3.59-3.50 (m, 4H),3.38-3.23 (m, 4H), 2.97-2.69 (m, 3H), 2.20-2.08 (m, 1H), 1.74-1.64 (m,2H), 1.59-1.48 (m, 2H), 1.47-1.39 (m, 2H), 1.37-1.29 (m, 10H); ¹³C NMR(101 MHz, CDCl₃): δ 170.97, 170.79, 169.51, 168.32, 167.89, 167.65,150.71 (dd, J=251.9, 10.9 Hz), 147.04, 146.51-146.34 (m), 144.21 (dd,J=247.4, 14.0 Hz), 144.63 (d, J=10.7 Hz), 136.12, 132.49, 125.32-125.17(m), 124.50 (dd, J=7.8, 4.0 Hz), 116.66, 112.45 (d, J=17.1 Hz), 111.36,109.82, 106.06, 72.43 (d, J=5.1 Hz), 66.14 (2C), 48.86, 48.57 (2C),42.65, 39.15, 31.43, 29.49, 29.39 (2C), 29.25, 29.22, 29.21, 26.90,26.84, 22.83. HRMS (ESI) m/z [M+H]+ calcd for C₃₈H₄₄F₂N₆O₇S 767.30330.found 767.30327.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide(Example 4)

General Procedure III was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.018 g, 0.049 mmol),4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (O) (0.022 g, 0.049 mmol), DIPEA (0.034 mL, 0.199 mmol)and HATU (0.024 g, 0.062 mmol) in dry DMF (1.0 mL) to afford the titledcompound as yellow solid (4.5 mg, 12% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 97:3) followed by HPLCpurification (Agilent Technologies 1200; column, Eclipse XDB-C18 4.6×150mm (5 μm); flow rate, 0.8 mL/min; DAD 190-650 nm; isocratic eluent,ACN/H₂O 70:30). ¹H NMR (400 MHz, CDCl₃): δ 8.44 (bs, 1H), 7.64 (t, J=6.5Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.36 (bs, 1H), 7.09 (d, J=7.1 Hz, 1H),7.05-6.95 (m, 2H), 6.83 (d, J=8.5 Hz, 1H), 6.51 (bs, 1H), 4.98-4.85 (m,1H), 4.56 (s, 2H), 3.93-3.80 (m, 4H), 3.77-3.64 (m, 8H), 3.62-3.51 (m,6H), 3.45-3.34 (m, 2H), 2.96-2.66 (m, 3H), 2.20-2.05 (m, 1H). HRMS (ESI)m/z [M+H]+ calcd for C₃₄H₃₆F₂N₆O₉S 74323053. found 743.23191.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide(Example 5)

General Procedure III was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.027 g, 0.076 mmol),4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (P) (0.037 g, 0.076 mmol), DIPEA (0.053 mL, 0.305 mmol)and HATU (0.036 g, 0.095 mmol) in dry DMF (1.0 mL) to afford the titledcompound as yellow solid (0.041 g, 69% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 98:2). ¹H NMR (400 MHz,CDCl₃): δ 8.31 (s, 1H), 7.66 (t, J=6.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H),7.12 (d, J=7.1 Hz, 1H), 7.09-6.96 (m, 3H), 6.91 (d, J=8.5 Hz, 1H), 6.48(t, J=4.8 Hz, 1H), 4.92 (dd, J=5.3, 11.9 Hz, 1H), 4.56 (s, 2H),3.97-3.81 (m, 6H), 3.81-3.22 (m, 18H), 3.07-2.58 (m, 3H), 2.16-2.06 (m,1H); ¹³C NMR (101 MHz, CDCl₃): δ 171.00, 170.63, 169.24, 168.30, 168.05,167.58, 150.54 (dd, J=11.4, 251.2 Hz), 146.79, 146.23-145.77 (m), 144.52(d, J=9.3 Hz), 144.29 (dd, J=13.9, 247.2 Hz), 136.02, 132.51, 125.28,124.43, 116.72, 112.53 (d, J=17.0 Hz), 111.66, 110.30, 106.35, 7226 (d,J=4.6 Hz), 70.77, 70.64, 70.60, 70.37, 69.58, 69.42, 66.14 (2C), 48.86,48.56 (2C), 42.37, 38.88, 31.42, 22.82. HRMS (ESI) m/z [M+H]+ calcd forC₃₆H₄₀F₂N₆O₁₀S 787.25675. found 787.25712.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)acetamide(Example 6)

General Procedure III was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.031 g, 0.087 mmol),4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (Q) (0.036 g, 0.087 mmol), DIPEA (0.06 mL, 0.348 mmol) andHATU (0.041 g, 0.108 mmol) in dry DMF (1.0 mL) to afford the titledcompound as yellow solid (0.03 g, 42% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 98:2). ¹H NMR (400 MHz,CDCl₃): δ 8.37 (s, 1H), 7.67 (ddd, J=2.2, 6.0, 8.7 Hz, 1H), 7.53-7.47(m, 1H), 7.39-7.32 (m, 1H), 7.12 (d, J=7.1 Hz, 1H), 7.05 (s, 1H),7.04-6.96 (m, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.50 (t, J=5.4 Hz, 1H),4.94-4.85 (m, 1H), 4.56 (s, 2H), 3.92-3.80 (m, 4H), 3.71 (t, J=5.4 Hz,2H), 3.69-3.50 (m, 16H), 3.54-3.50 (m, 4H), 3.46 (q, J=5.4 Hz, 2H),2.92-2.65 (m, 3H), 2.17-2.09 (m, 1H); ¹³C NMR (101 MHz, CDCl₃): δ 171.09(d, J=2.8 Hz), 170.60, 169.22, 168.38, 168.00, 167.57, 150.49 (dd,J=11.4, 250.9 Hz), 146.81, 145.99, 144.52 (d, J=9.5 Hz), 144.30 (dd,J=14.0, 247.3 Hz), 136.02, 132.51, 125.38, 124.41 (dd, J=4.1, 7.7 Hz),116.74, 112.50 (d, J=17.1 Hz), 111.64, 110.29, 106.44, 72.22 (d, J=4.7Hz), 70.75, 70.63, 70.59, 70.53, 70.43, 70.39, 69.67, 69.41, 66.15 (2C),48.84, 48.52 (2C), 42.37, 38.86, 31.39, 22.82. HRMS (ESI) m/z [M+H]+calcd for C₃₈H₄₄F₂N₆O₁₁S 831.28296. found 831.28447.

2-(2,6-Dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (R)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.The solution of 3-hydroxyphthalic anhydride (0.50 g, 3.05 mmol) and3-aminopiperidine-2,6-dione hydrochloride (0.50 g, 3.05 mmol) inpyridine (12.0 mL) was stirred at 110° C. overnight. After cooling, themixture was cooled to rt and concentrated under reduced pressure. Thecrude was purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5) to give the titled compound as light-yellow solid (0.7 g, 84%yield). ¹H NMR (400 MHz, DMSO-d₄): δ 11.16 (bs, 1H), 7.66 (dd, J=8.2 and7.3 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.08 (dd,J=12.8 and 5.4 Hz, 1H), 2.99-2.81 (m, 1H), 2.69-2.53 (m, 2H), 2.12-1.95(m, 1H); ¹³C NMR (101 MHz, DMSO-d₆): δ 173.27, 170.48, 167.48, 166.27,155.95, 136.84, 133.60, 124.02, 114.81, 114.73, 49.09, 31.42, 22.49.

Tert-butyl2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (S)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.To the solution of2-(2,6-dioxopiperidin-3-yl)-4-hydoxyisoindoline-1,3-dione (R)(0.50 g,1.82 mmol) in dry DMF (4.0 mL) were added K₂CO₃ (0.37 g, 2.73 mmol) andtert-butyl bromoacetate (0.27 mL, 1.82 mmol). The mixture was stirred atrt for 2 h. Then, it was poured in ice-water yielding a precipitatewhich was filtered and purified by flash column chromatography on SiO₂(PE/EA, 6:4) to afford the titled compound as light-yellow solid (0.258g, 42% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.37 (bs, 1H), 7.67 (t, J=7.9Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.99 (dd,J=11.8 and 5.4 Hz, 1H), 4.80 (s, 2H), 2.95-2.71 (m, 3H), 2.19-2.06 (m,1H), 1.49 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 171.09, 168.02, 166.88,166.84, 165.46, 155.50, 136.29, 133.90, 119.75, 117.56, 116.90, 83.12,77.37, 77.05, 76.73, 66.52, 49.17, 31.38, 28.03 (3C), 22.57.

2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic Acid(E3LB-2)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.Tert-butyl2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate(S)(1.75 g, 4.51 mmol) was dissolved in 4N HCl in dioxane (15 mL, 0.1M)and stirred at rt overnight. The solvent was evaporated under reducedpressure and the crude residue was tritured with DEE affording thetitled compound as white solid (1.26 g, 84% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 13.25 (s, 1H), 11.12 (s, 1H), 7.87-7.73 (m, 1H), 7.48 (d,J=7.2 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 5.11 (dd, J=12.7 and 5.4 Hz, 1H),5.00 (s, 2H), 2.96-2.82 (m, 1H), 2.72-2.54 (m, 2H), 2.11-1.98 (m, 1H);¹³C NMR (101 MHz, DMSO-d₆): δ 173.27, 170.39, 169.98, 167.21, 165.64,155.60, 137.23, 133.72, 120.33, 116.78, 116.23, 65.44, 49.25, 31.41,22.43.

General Procedure IV: HATU-Mediated Amidation Reaction Tert-butyl(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexyl)carbamate(T)

The titled compound can be prepared according to the process describedby Bradner, J. et al. U.S. Pat. Appl. Publ., US20160176916. In anoven-dried round-bottom flask, under nitrogen atmosphere, to a stirredsolution of2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(E3LB-2) (0.020 g, 0.060 mmol, 1.0 equiv), tert-butyl(6-aminohexyl)carbamate (0.014 g, 0.066 mmol, 1.1 equiv), and DIPEA(0.02 mL, 0.120 mmol, 2.0 equiv) in dry THF (1.5 mL) was added HATU(0.027 g, 0.072 mmol, 1.20 equiv). Stirring was continued at rtovernight. The reaction mixture was evaporated to dryness ad the cruderesidue was purified by flash column chromatography on SiO₂(DCM/Acetone, 6:4) to give the titled compound as white solid (0.02 g,62% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.80 (s, 1H), 7.77 (dd, J=8.4,7.4 Hz, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.51-7.44 (m, 1H), 7.22 (d, J=8.3Hz, 1H), 5.01 (dd, J=12.3, 5.5 Hz, 1H), 4.66 (s, 2H), 3.52-3.29 (m, 2H),3.23-3.02 (m, J=18.9 Hz, 2H), 3.00-2.79 (m, 3H), 2.26-2.14 (m, 1H),1.65-1.57 (m, 2H), 1.54-1.35 (m, 15H); ¹³C NMR (101 MHz, CDCl₃): δ171.03, 168.12, 166.64, 166.61, 166.05, 156.21, 154.52, 137.05, 133.60,119.55, 118.20, 117.41, 87.18, 68.05, 49.34, 40.62, 39.09, 31.49, 30.01,29.05, 28.43 (3C), 26.50 (2C), 22.68.

Tert-butyl(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)carbamate(U)

The titled compound can be prepared according to the process describedby Remillard, D. et al. Angew. Chem. Int. Ed. Engl. 2017, 56, 5738-5743.General Procedure IV (4 h) was followed by using2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(E3LB-2) (0.250 g, 0.752 mmol), tert-butyl (8-aminooctyl)carbamate(0.202 g, 0.827 mmol), DIPEA (0.26 mL, 1.505 mmol) and HATU (0.343 g,0.903 mmol) in dry DMF (3.0 mL) to afford the titled compound aslight-yellow solid (0.140 g, 33% yield) following purification by flashcolumn chromatography on SiO₂ (DCM/Acetone, 85:15 to 70:30). ¹H NMR (400MHz, CDCl₃): δ 8.46 (s, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.2 Hz,1H), 7.42 (t, J=5.3 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 4.99 (dd, J=12.1,5.4 Hz, 1H), 4.66 (s, 2H), 4.62 (s, 1H), 3.39 (dd, J=12.9, 6.7 Hz, 2H),3.20-3.04 (m, 2H), 3.02-2.73 (m, 3H), 2.25-2.11 (m, 1H), 1.71-1.57 (m,4H), 1.46 (s, 11H), 1.37-1.27 (m, 6H); ¹³C NMR (101 MHz, CDCl₃): δ170.81, 167.94, 166.63, 166.57, 165.95, 156.05, 154.51, 137.05, 133.59,119.47, 118.12, 117.38, 68.00, 49.34, 39.18 (2C), 31.50, 30.01, 29.24,29.15, 29.13, 28.43 (3C), 26.92, 26.68, 26.63, 22.58.

Tert-butyl(10-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)carbamate(V)

General Procedure IV (overnight) was followed by using2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(E3LB-2) (0.250 g, 0.752 mmol), tert-butyl (10-aminodecyl)carbamate(0.205 g, 0.752 mmol), DIPEA (0.25 mL, 1.505 mmol) and HATU (0.343 g,0.903 mmol) in dry THF (5.0 mL) to afford the titled compound as whitesolid (0.220 g, 50% yield) following double purification by flash columnchromatography on SiO₂ (first: DCM/Acetone, 80:20; second: DCM/MeOH,96:4). ¹H NMR (400 MHz, CDCl₃): δ 8.25 (bs, 1H), 7.83-7.74 (m, 1H), 7.58(d, J=7.3 Hz, 1H), 7.43-7.36 (m, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.99 (dd,J=12.3 and 5.2 Hz, 1H), 4.66 (s, 2H), 4.57 (s, 1H), 3.46-3.32 (m, 2H),3.19-3.04 (m, 2H), 3.02-2.72 (m, 3H), 2.29-2.08 (m, 1H), 1.71-1.55 (m,4H), 1.46 (s, 9H), 1.42-1.20 (m, 12H); ¹³C NMR (101 MHz, CDCl₃): δ171.56, 170.69, 167.85, 166.61, 166.53, 165.93, 154.52, 137.06, 133.58,119.45, 118.09, 117.37, 68.01, 49.31, 40.59, 39.24, 31.47, 30.05, 29.45,29.42, 29.34, 29.24, 29.22, 28.44 (3C), 26.79, 26.73, 22.58.

Tert-butyl(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioza-3-azatetradecan-14-yl)carbamate(Y)

General Procedure IV (overnight) was followed by using2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(E3LB-2) (0.129 g, 0.388 mmol), tert-butyl(14-amino-3,6,9,12-tetraoxatetradec-1-yl)carbamate (0.130 g, 0.388mmol), DIPEA (0.132 mL, 0.776 mmol) and HATU (0.177 g, 0.466 mmol) indry THF (2.5 mL) to afford the titled compound as white solid (0.124 g,49% yield) following purification by flash column chromatography on SiO₂(DCM/MeOH, 97:3). ¹H NMR (400 MHz, CDCl₃): δ 8.90 (bs, 1H), 7.77 (t,J=7.9 Hz, 1H), 7.68 (bs, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.21 (d, J=8.4 Hz,1H), 5.23 (bs, 1H), 4.98 (dd, J=11.9 and 5.3 Hz, 1H), 4.67 (s, 2H),3.79-3.55 (m, 14H), 3.31 (t, J=4.8 Hz, 2H), 2.99-2.69 (m, 3H), 2.27-2.11(m, 1H), 1.46 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 171.27, 168.28,166.92, 166.65, 165.83, 156.10, 154.44, 137.03, 133.64, 119.40, 118.02,117.31, 79.24, 70.34 (2C), 70.28 (2C), 70.23, 69.43, 67.88, 55.75,43.68, 39.11, 31.38, 28.42 (3C), 22.71.

N-(6-Aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (Z)

General Procedure II (overnight) was followed by using tert-butyl(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexyl)carbamate(T)(0.090 g, 0.169 mmol) and 4N HCl in dioxane (1.0 mL) to afford thetitled compound as white solid (0.070 g, 89% yield). ¹H NMR (400 MHz,MeOD): δ 7.84 (dd, J=8.4 and 7.4 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.46(d, J=8.5 Hz, 1H), 5.16 (dd, J=12.5 and 5.5 Hz, 1H), 4.79 (s, 2H),3.40-3.34 (m, 2H), 2.98-2.63 (m, 5H), 2.23-2.12 (m, 1H), 1.72-1.58 (m,4H), 1.50-1.39 (m, 4H).

N-(8-Aminooctyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AA)

General Procedure II (4 h) was followed by using tert-butyl(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)carbamate(U)(0.116 g, 0.208 mmol) and 4N HCl in dioxane (1.1 mL) to afford thetitled compound as white solid (0.096 g, 93% yield). ¹H NMR (400 MHz,MeOD): δ 7.83 (t, J=7.9 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 5.16 (dd, J=12.5, 5.5 Hz, 1H), 4.78 (s, 2H), 3.00-2.67 (m, 5H),2.25-2.12 (m, 1H), 1.73-1.54 (m, 4H), 1.47-1.37 (m, 10H).

N-(10-Aminodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AB)

General Procedure II (5 h) was followed by using tert-butyl(10-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)carbamate(V)(0.210 g, 0.358 mmol) and 4N HCl in dioxane (2.0 mL) to afford thetitled compound as white solid (0.175 g, 93% yield). ¹H NMR (400 MHz,MeOD): δ 8.07 (t, J=5.6 Hz, 1H), 7.88-7.80 (m, 1H), 7.56 (d, J=7.3 Hz,1H), 7.45 (d, J=8.5 Hz, 1H), 5.16 (dd, J=12.6, 5.4 Hz, 1H), 4.78 (s,2H), 3.00-2.68 (m, 5H), 2.26-2.11 (m, 1H), 1.75-1.53 (m, 4H), 1.47-1.27(m, 12H).

N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AC)

General Procedure II (overnight) was followed by using tert-butyl(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl)carbamate(W) (synthesized according to the process described by Bradner, J. etal. U.S. Pat. Appl. Publ., US20160176916) (0.125 g, 0.222 mmol) and 4NHCl in dioxane (1.0 mL) to afford the titled compound as white solid(0.076 g, 70% yield). ¹H NMR (400 MHz, MeOD): δ 7.83 (t, J=7.9 Hz, 1H),7.54 (d, J=7.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 5.16 (dd, J=12.7, 5.5Hz, 1H), 4.80 (s, 2H), 3.77-3.63 (m, 8H), 3.54 (t, J=5.2 Hz, 2H),3.18-3.10 (m, 2H), 2.99-2.66 (m, 3H), 2.25-2.13 (m, 1H).

N-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AD)

General Procedure II (overnight) was followed by using tert-butyl(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(Y) (0.145 g, 0.239 mmol) and 4N HCl in dioxane (1.0 mL) to afford thetitled compound as light-yellow solid (0.104 g, 80% yield). ¹H NMR (400MHz, MeOD): δ 7.95-7.77 (m, 1H), 7.67-7.54 (m, 1H), 7.51-7.38 (m, 1H),5.23-5.11 (m, 1H), 4.80 (s, 2H), 3.59-3.49 (m, 2H), 3.33 (s, 4H), 3.14(s, 2H), 3.04-2.62 (m, 3H), 2.29-2.06 (m, 1H).

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexyl)acetamide(Example 7)

General Procedure III (16 h) was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.023 g, 0.064 mmol),N-(6-aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (Z) (0.030 g, 0.064 mmol), DIPEA (0.044 mL, 0.257 mmol),and HATU (0.030 g, 0.080 mmol) in dry DMF (1.0 mL) to afford the titledcompound as white solid (0.002 g, 4.6% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 97:3). ¹H NMR (400 MHz,CDCl₃): δ 9.03 (bs, 1H), 7.82-7.73 (m, 1H), 7.65-7.47 (m, 3H), 7.21 (d,J=8.4 Hz, 1H), 7.14 (bs, 1H), 6.99 (dd, J=16.7, 9.1 Hz, 1H), 6.93 (s,1H), 4.99 (dd, J=12.1, 5.3 Hz, 1H), 4.65 (s, 2H), 4.60 (s, 2H),3.91-3.80 (m, 4H), 3.59-3.50 (m, 4H), 3.50-3.22 (m, 4H), 3.03-2.70 (m,3H), 2.24-2.09 (m, 1H), 1.53-1.16 (m, 8H). HRMS (ESI) m/z [M+H]+ calcdfor C₃₆H₃₈F₂N₆O₉S 769.24618. found 769.24848.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)acetamide(Example 8)

General Procedure III (16 h) was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.032 g, 0.091 mmol),N-(8-aminooctyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AA)(0.045 g, 0.091 mmol), DIPEA (0.062 mL, 0.363 mmol),and HATU (0.043 g, 0.114 mmol) in dry DMF (2.0 mL) to afford the titledcompound as yellow solid (0.012 g, 17% yield) following purification byflash column chromatography on SiO₂ (DCM/Acetone, 75:25). ¹H NMR (400MHz, CDCl₃): δ 8.66 (bs, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.66-7.53 (m, 2H),7.49-7.39 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.08-6.90 (m, 3H), 4.98 (dd,J=12.0, 5.0 Hz, 1H), 4.65 (s, 2H), 4.60 (s, 2H), 3.94-3.78 (m, 4H),3.60-3.47 (m, 4H), 3.40-3.25 (m, 4H), 3.02-2.73 (m, 3H), 2.26-2.12 (m,1H), 1.56-1.47 (m, 2H), 1.45-1.28 (m, 10H); ¹³C NMR (101 MHz, CDCl₃): δ170.91, 170.82, 168.05, 167.97, 166.64, 166.57, 165.99, 154.51, 150.69(dd, J=251.69 and 11.5 Hz), 146.51-146.44 (m), 144.19 (dd, J=47.3, 14.0Hz), 144.63 (d, J=10.6 Hz), 137.04, 133.60, 125.25 (d, J=3.5 Hz), 124.47(dd, J=7.6, 4.3 Hz), 119.47, 118.14, 117.38, 112.41 (d, J=17.1 Hz),106.11, 72.41 (d, J=5.1 Hz), 68.01, 66.13 (2C), 49.34, 48.55 (2C),39.16, 39.10, 31.49, 29.44, 29.23, 29.13, 29.06, 26.70, 26.68, 22.59.HRMS (ESI) m/z [M+H]+ calcd for C₃₈H₄₂F₂N₆O₉S 797.27748. found797.27834.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(10-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)acetamide(Example 9)

General Procedure III (6 h) was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.031 g, 0.086 mmol),N-(10-aminodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AB) (0.045 g, 0.086 mmol), DIPEA (0.059 mL, 0.344 mmol),and HATU (0.041 g, 0.107 mmol) in dry DMF (1.0 mL) to afford the titledcompound as white solid (0.041 g, 58% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 97:3). ¹H NMR (400 MHz,CDCl₃): δ 8.42 (s, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.69-7.48 (m, 2H), 7.40(s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.13-6.96 (m, 2H), 6.94 (s, 1H), 4.98(dd, J=5.1, 12.2 Hz, 1H), 4.65 (s, 2H), 4.60 (s, 2H), 4.04-3.71 (m, 4H),3.71-3.45 (m, 4H), 3.35 (dq, J=6.2, 6.7, 20.5 Hz, 4H), 3.12-2.68 (m,3H), 2.27-2.03 (m, 1H), 1.55-1.44 (m, 4H), 1.44-1.16 (m, 12H); ¹³C NMR(101 MHz, CDCl₃): δ 170.77 (2C), 167.90 (2C), 166.61, 166.55, 165.95,154.51, 150.71 (dd, J=11.5, 251.2 Hz), 146.39 (d, J=2.5 Hz), 144.62 (d,J=9.7 Hz), 144.17 (dd, J=14.1, 247.4 Hz), 137.05, 133.58, 125.18 (d,J=2.8 Hz), 124.47 (dd, J=4.0, 7.7 Hz), 119.46, 118.09, 117.37, 112.38(d, J=17.1 Hz), 106.06, 72.40 (d, J=5.2 Hz), 68.01, 66.12 (2C), 49.32,48.56 (2C), 39.25, 39.08, 31.47, 29.46, 29.41, 29.40, 29.33, 29.21,29.20, 26.79, 26.77, 22.58. HRMS (ESI) m/z [M+H]+ calcd forC₄₀H₄₆F₂N₆O₉S 825.30878. found 825.30942.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl)acetamide(Example 10)

General Procedure III (16 h) was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.025 g, 0.070 mmol),N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AC) (0.035 g, 0.070 mmol), DIPEA (0.048 mL, 0.280 mmol),and HATU (0.033 g, 0.087 mmol) in dry DMF (2.0 mL) to afford the titledcompound as light-yellow solid (0.009 g, 17% yield) followingpurification by flash column chromatography on SiO₂ (DCM/MeOH, 97:3). ¹HNMR (400 MHz, CDCl₃): δ 8.75 (bs, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.68-7.52(m, 3H), 7.40 (bs, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.07-6.91 (m, 2H), 4.96(dd, J=11.7, 5.1 Hz, 1H), 4.63 (s, 2H), 4.58 (s, 2H), 3.94-3.80 (m, 4H),3.79-3.63 (m, 8H), 3.60-3.43 (m, 8H), 2.97-2.64 (m, 3H), 2.22-2.10 (m,1H). HRMS (ESI) m/z [M+H]+ calcd for C₃₆H₃₈F₂N₆O₁₁S 801.23601. found801.23745.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)acetamide(Example 11)

General Procedure III (16 h) was followed by using2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid(E)(0.033 g, 0.092 mmol),N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamidehydrochloride (AD) (0.050 g, 0.092 mmol), DIPEA (0.063 mL, 0.368 mmol),and HATU (0.043 g, 0.115 mmol) in dry DMF (2.0 mL) to afford the titledcompound as light-yellow solid (0.012 g, 16% yield) followingpurification by flash column chromatography on SiO₂ (DCM/MeOH, 97:3). ¹HNMR (400 MHz, CDCl₃): δ 8.96 (bs, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.70-7.59(m, 2H), 7.55 (d, J=7.3 Hz, 1H), 7.46 (bs, 1H), 7.18 (d, J=8.4 Hz, 1H),7.08 (s, 1H), 6.98 (dd, J=16.7, 9.0 Hz, 1H), 4.92 (dd, J=12.1, 5.3 Hz,1H), 4.64 (s, 2H), 4.56 (s, 2H), 3.90-3.82 (m, 4H), 3.71-3.47 (m, 20H),2.92-2.61 (m, 3H), 2.19-2.07 (m, 1H). HRMS (ESI) m/z [M+H]+ calcd forC₃₈H₄₂F₂N₆O₁₂S 845.26222. found 845.26303.

General Procedure V: Mitsunobu Reaction Tert-butyl(2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate(AE)

DIAD (0.087 mL, 0.442 mmol, 1.1 equiv) was slowly added to a stirredice-cooled solution of 2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol(ARB-1) (0.120 g, 0.402 mmol, 1.0 equiv), tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (0.110 g, 0.442 mmol, 1.1equiv), and PPh₃ (0.116 g, 0.442 mmol, 1.1 equiv) in dry THF (5.0 mL).The solution was stirred at 0° C. for 30 min, then at rt for 16 h. Thereaction mixture was quenched with water (20 mL) and extracted with EA(10 mL×3). Reunited organic phases were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford a crude residue which waspurified by flash column chromatography on SiO₂ (DCM/EA, 9:1 to 8:2) togive the titled compound as yellow oil (0.100 g, 70% yield). ¹H NMR (400MHz, DMSO-d₆): δ 7.89 (ddd, J=8.8, 6.3, 2.3 Hz, 1H), 7.58 (s, 1H),7.00-6.88 (m, 1H), 5.10-4.94 (m, 1H), 4.35-4.24 (m, 2H), 3.92-3.79 (m,6H), 3.72-3.61 (m, 4H), 3.60-3.48 (m, 6H), 3.39-3.25 (m, 2H), 1.43 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 169.71, 155.99, 150.35 (dd, J=11.6,249.5 Hz), 145.52, 144.65 (dd, J=13.6, 246.2 Hz), 125.04 (d, J=2.1 Hz),123.84 (dd, J=4.0, 7.8 Hz), 111.42 (d, J=17.0 Hz), 107.47, 79.17, 72.56(d, J=6.0 Hz), 70.46, 70.34, 70.30 (2C), 66.22 (2C), 48.60 (2C), 40.35,28.39 (3C).

Tert-butyl(2-(2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate(AF)

General Procedure V was followed by using DIAD (0.087 mL, 0.442 mmol),2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol (ARB-1) (0.120 g, 0.402mmol), tert-butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (0.130 g, 0.442mmol), and PPh₃ (0.116 g, 0.442 mmol) in dry THE (5.0 mL) to afford thetitled compound as yellow oil, which solidified upon standing at rt(0.148 g, 93% yield) following purification by flash columnchromatography on SiO₂ (DCM/EA, 7:3). ¹H NMR (400 MHz, DMSO-d₆): δ7.90(ddd, J=8.9, 6.3, 2.3 Hz, 1H), 7.57 (s, 1H), 6.99-6.90 (m, 1H), 5.02 (s,1H), 4.36-4.26 (m, 2H), 3.93-3.82 (m, 6H), 3.75-3.59 (m, 8H), 3.58-3.49(m, 6H), 3.39-3.25 (m, 2H), 1.46 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ169.70, 155.98, 150.35 (dd, J=11.7, 249.5 Hz), 145.54, 144.63 (dd,J=13.7, 246.3 Hz), 125.02 (d, J=3.2 Hz), 123.83 (dd, J=3.9, 7.8 Hz),111.38 (d, J=17.0 Hz), 107.48, 79.16, 72.60 (d, J=6.0 Hz), 70.64, 70.60,70.58, 70.28, 70.23 (2C), 66.21 (2C), 48.59 (2C), 40.35, 28.41 (3C).

Tert-butyl(14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate (AG)

General Procedure V was followed by using DIAD (0.040 mL, 0.201 mmol),2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol (ARB-1) (0.05 g, 0.167mmol), tert-butyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl)carbamate(0.062 g, 0.184 mmol), and PPh₃ (0.526 g, 0.201 mmol) in dry THF (2.0mL) to afford the titled compound as white solid (0.039 g, 37% yield)following double purification by flash column chromatography (first onSiO₂:DCM/Acetone, 95:5 to 90:10; second on Silica RP-18: water/ACN,5:5). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (ddd, J=2.3, 6.3, 8.8 Hz, 1H),7.57 (s, 1H), 7.03-6.85 (m, 1H), 5.06 (s, 1H), 4.41-4.14 (m, 2H),3.95-3.77 (m, 6H), 3.77-3.59 (m, 12H), 3.53 (q, J=4.9, 5.3 Hz, 6H), 3.31(d, J=5.1 Hz, 2H), 1.45 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 169.69,155.99, 150.33 (dd, J=11.7, 249.5 Hz), 145.53, 144.62 (dd, J=13.7, 246.3Hz), 125.00, 123.81 (dd, J=4.0, 7.8 Hz), 111.36 (d, J=17.0 Hz), 107.51,79.15, 72.60 (d, J=6.0 Hz), 70.65, 70.63, 70.59, 70.55, 70.52, 70.26,70.23 (2C), 66.21 (2C), 48.59 (2C), 40.35, 28.42 (3C).

2-(2-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AH)

General Procedure II (overnight) was followed by using tert-butyl(2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate(AE) (0.100 g, 0.189 mmol) and 4N HCl in dioxane (2.0 mL) to afford thetitled compound as white solid (0.080 g, 91% yield). ¹H NMR (400 MHz,MeOD): δ 7.49-7.40 (m, 1H), 7.28 (s, 1H), 7.04 (dd, J=16.9, 9.0 Hz, 1H),4.25 (s, 1H), 3.86-3.50 (m, 18H), 3.02 (s, 2H).

2-(2-(2-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AI)

General Procedure II (overnight) was followed by using tert-butyl(2-(2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate(AF) (0.140 g, 0.244 mmol) and 4N HCl in dioxane (2.0 mL) to afford thetitled compound as white solid (0.115 g, 93% yield). ¹H NMR (400 MHz,MeOD): δ 7.59 (s, 1H), 7.43 (s, 1H), 7.15 (dd, J=16.8, 8.8 Hz, 1H), 4.39(s, 2H), 3.91 (s, 4H), 3.82 (s, 2H), 3.77-3.55 (m, 14H), 3.15 (s, 2H).

4-((2-(2-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Example 12)

General Procedure I (6 h) was followed by using2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AH) (0.044 g, 0.095 mmol),2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.024 g, 0.086 mmol), and DIPEA (0.044 mL, 0.256 mmol) in dry DMF (0.6mL) to afford the titled compound as yellow solid (0.06 g, 54% yield)following purification by flash column chromatography on SiO₂(DCM/Acetone, 9:1). ¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 7.89 (ddd,J=8.7, 6.3, 2.1 Hz, 1H), 7.58 (s, 1H), 7.52-7.44 (m, 1H), 7.11 (d, J=7.1Hz, 1H), 6.99-6.88 (m, 2H), 6.51 (t, J=5.3 Hz, 1H), 4.90 (dd, J=12.1,5.3 Hz, 1H), 4.40-4.24 (m, 2H), 3.98-3.81 (m, 6H), 3.79-3.62 (m, 6H),3.59-3.38 (m, 6H), 2.96-2.65 (m, 3H), 2.19-2.03 (m, 1H). HRMS (ESI) m/z[M+H]+ calcd for C₃₂H₃₃F₂N₅O₈S 686.20907. found 686.20855.

4-((2-(2-(2-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Example 13)

General Procedure I (6 h) was followed by using2-(2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AI) (0.050 g, 0.098 mmol),2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (E3LB-1)(0.024 g, 0.086 mmol) and DIPEA (0.044 mL, 0.256 mmol) in dry DMF (0.6mL) to afford the titled compound as yellow solid (0.034 g, 53% yield)following purification by flash column chromatography on SiO₂(DCM/Acetone, 9:1). ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.88 (ddd,J=8.7, 6.3, 2.1 Hz, 1H), 7.57 (s, 1H), 7.52-7.44 (m, 1H), 7.11 (d, J=7.1Hz, 1H), 6.98-6.87 (m, 2H), 6.49 (t, J=5.4 Hz, 1H), 4.91 (dd, J=12.0,5.3 Hz, 1H), 4.34-4.22 (m, 2H), 3.92-3.81 (m, 6H), 3.79-3.60 (m, 10H),3.58-3.40 (m, 6H), 2.96-2.62 (m, 3H), 2.15-2.06 (m, 1H); ¹³C NMR (101MHz, CDCl₃): δ 170.98, 169.73, 169.25, 168.29, 167.60, 150.36 (dd,J=11.5, 249.7 Hz), 146.85, 145.64-145.34 (m), 144.64 (dd, J=13.6, 246.2Hz), 136.04, 132.49, 124.99 (d, J=2.8 Hz), 123.84 (dd, J=4.0, 7.8 Hz),116.77, 111.66, 111.40 (d, J=17.0 Hz), 110.27, 107.55, 72.65 (d, J=6.0Hz), 70.73 (3C), 70.57, 70.26, 69.54, 66.21 (2C), 48.86, 48.60 (2C),42.42, 31.41, 22.77. HRMS (ESI) m/z [M+H]+ calcd for C₃H₃₇F₂N₅O₉S730.23528. found 730.23653.

N-(14-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide(Example 14)

General Procedure II (overnight) was followed by using tert-butyl(14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate (AG)(0.039 g, 0.063 mmol) and 4N HCl in dioxane (2.0 mL) toafford14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-aminehydrochloride (AJ) as white solid (0.034 g, 98% yield). Then, undernitrogen atmosphere, to the solution of2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(E3LB-2) (0.023 g, 0.069 mmol),14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-aminehydrochloride (AJ) (0.035 g, 0.063 mmol), and DIPEA (0.035 mL, 0.205mmol) in dry DMF was added HATU (0.046 g, 0.08 mmol) and the mixture wasstirred at rt overnight. The reaction mixture was poured in ice-waterand extracted with EA (10 mL×3). Reunited organic phases were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford acrude residue which was purified by HPLC (Agilent Technologies 1200;column, Eclipse XDB-C18 4.6×150 mm (5 μm); flow rate, 1.0 mL/min; DAD190-650 nm; isocratic eluent, ACN/H₂O 70:30) to afford the titledcompound as white solid (5.5 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃): δ8.82 (s, 1H), 7.89 (ddd, J=2.3, 6.2, 8.8 Hz, 1H), 7.82-7.70 (m, 1H),7.70-7.61 (m, 1H), 7.56 (d, J=7.0 Hz, 1H), 7.54 (s, 1H), 7.20 (d, J=8.2Hz, 1H), 7.04-6.85 (m, 1H), 4.99-4.81 (m, 1H), 4.66 (s, 2H), 4.42-4.20(m, 2H), 3.91-3.79 (m, 6H), 3.79-3.44 (m, 20H), 3.01-2.67 (m, 3H),2.28-2.01 (m, 1H); ¹³C NMR (101 MHz, CDCl₃): δ 170.94, 169.73, 168.03,166.75, 166.60, 165.75, 154.40, 150.35 (dd, J=11.6, 249.7 Hz),145.63-145.21 (m), 144.63 (dd, J=13.7, 246.2 Hz), 136.93, 133.68,125.00, 123.82 (dd, J=3.9, 7.9 Hz), 119.23, 118.04, 117.26, 111.42 (d,J=17.0 Hz), 107.50, 72.62 (d, J=5.9 Hz), 70.77, 70.48, 70.46 (2C),70.35, 70.29, 70.20, 69.45, 67.83, 66.22 (2C), 49.28, 48.59 (2C), 39.09,31.41, 22.72. HRMS (ESI) m/z [M+H]+ calcd for C₃₈H₄₃F₂N₅O₁₂S 832.26698.found 832.26587.

Tert-butyl (S)-1-(4-bromophenyl)ethyl)carbamate (AK)

The titled compound can be prepared according to the process describedby Kanak Raina et al. Proc. Natl. Acad. Sci. USA. 2016, 113, 7124-7129.To a mixture of(S)-1-(4-bromophenyl)ethanamine (commercially availablefrom, for example, Fluorochem) (3.98 g, 19.89 mmol) and NaHCO₃ (1.25 g,14.92 mmol) in water (10 mL) and EA (10 mL) was added (Boc)₂O (5.20 g,23.87 mmol) by maintaining the temperature at 5° C. After stirring at rtfor 2 h, the reaction mixture was filtered. The collected solid wassuspended in a mixture of hexane (10 mL) and water (10 mL) for 30 min.The solid was filtered and dried in an oven at 50° C. to afford thetitled compound as a white solid (5.41 g, 91% yield). ¹H NMR (400 MHz,CDCl₃): δ 7.55-7.39 (m, 2H), 7.19 (d, J=8.3 Hz, 2H), 4.99-4.46 (m, 2H),1.58-1.22 (m, 12H); ¹³C NMR (101 MHz, CDCl₃): δ 154.98, 143.26, 131.60(2C), 127.60 (2C), 120.80, 79.61, 49.68, 28.36 (3C), 22.61.

Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (AL)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.Under nitrogen atmosphere, a mixture of compound tert-butyl(S)-1-(4-bromophenyl)ethyl)carbamate (AK) (5.00 g, 16.65 mmol),4-methylthiazole (commercially available from, for example, Fluorochem)(3.30 g, 33.31 mmol), palladium (II) acetate (0.037 g, 0.166 mmol), andpotassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) was stirred at90° C. for 18 h. After cooling, the reaction mixture was filtered. Water(60 mL) was added to the filtrate, and the resulting mixture was stirredat rt for 4 h. The solid was collected by filtration and dried in anoven at 50° C. to afford the titled compound (3.14 g, 74% yield) as agray solid. ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H),7.41-7.35 (m, 2H), 4.86 (bs, 2H), 2.56 (s, 3H), 1.50 (d, J=6.5 Hz, 3H),1.46 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 155.06, 150.20, 148.48,131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39(3C), 22.71, 16.11.

(S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (AM)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129. Asolution of 4N HCl in dioxane (10 mL) was added to tert-butyl(S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (AL) (3.00 g,9.42 mmol). The reaction mixture was stirred at rt for 3 h. The solventwas evaporated to dryness, and the residue was triturated with DEE,filtered, and dried in an oven at 60° C. to afford the titled product(2.37 g, 99% yield) as a light-yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J=6.8 Hz, 3H); ¹³CNMR (101 MHz, DMSO-d_(d)): δ 152.95, 147.68, 139.93, 131.97, 131.49,129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03.

Methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (AN)

The titled compound can be prepared according to the process describedby Gmez-Bengoa E. et al. Chemistry 2010, 16, 5333-5342. Tionyl chloride(2.12 mL, 3.48 g, 29.2 mmol) was slowly added dropwise under nitrogenatmosphere to a stirred suspension of(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (commercially availablefrom, for example, Fluorochem) (3.20 g, 24.4 mmol) in dry MeOH (60.0 mL)at 0° C. After stirring overnight at rt, the solvent was evaporated todryness and the crude residue was tritured with DEE, filtered, and driedto afford the titled product as white solid (4.43 g, 100% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 9.78 (s, 2H), 5.58 (s, 1H), 4.48 (dd, J=7.5, 10.8Hz, 1H), 4.45-4.39 (m, 1H), 3.77 (s, 3H), 3.39-3.34 (m, 1H), 3.11-3.01(m, 1H), 2.26-2.01 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆): δ 169.54, 68.88,57.87, 53.54, 53.47, 37.43.

Methyl(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate(AO)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.Under nitrogen atmosphere, to a solution of(S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (commerciallyavailable from, for example, Fluorochem)(5.09 g, 22.02 mmol), methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (AN) (4.00 g,22.02 mmol), and DIPEA (13.43 mL, 9.97 g, 77.08 mmol) in dry DMF (40 mL)was added HATU (9.20 g, 21.2 mmol) at 0° C. The resulting mixture wasallowed to warm to rt and stirred for 16 h. The reaction mixture wasdropped in water (200 mL) and extracted with EA (100 mL×3). The combinedorganic phases were washed with water (100 mL×3), 1N HCl (100 mL×2),saturated NaHCO₃ solution (100 mL×2), brine (100 mL×2), dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford thetitled product as a light-yellow oil (7.66 g, 98% yield). ¹H NMR (400MHz, CDCl₃): δ 5.27 (d, J=9.4 Hz, 1H), 4.71 (t, J=8.6 Hz, 1H), 4.53 (s,1H), 4.21 (d, J=9.5 Hz, 1H), 4.14-4.01 (m, 1H), 3.75 (s, 3H), 3.78-3.68(m, 1H), 2.30 (s, 1H), 2.45-0.89 (m, 2H), 1.43 (s, 9H), 1.06 (s, 9H).¹³C NMR (101 MHz, CDCl₃): δ 172.6, 171.2, 156.3, 80.0, 70.3, 58.7, 57.4,56.3, 52.2, 37.6, 35.2, 28.3 (3C), 26.3 (3C).

(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (AP)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Nat. Acad. Sci. U.S.A. 2016, 113, 7124-7129. Tothe solution of methyl(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate(AO)(2.00 g, 5.58 mmol) in THF (20 mL) at 0° C. was added the solutionof lithium hydroxide monohydrate (2.34 g, 55.79 mmol) in water (10 mL).The resulting mixture was stirred at rt for 18 h. The organic solventwas removed under vacuo, the residue was diluted with ice-water (10 mL)and the pH was slowly adjusted to 2-3 with 2N HCl yielding a solid whichwas collected by filtration, washed with water (6 mL×2), and then driedin an oven at 50° C. to afford the titled compound as a white solid(1.45 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (bs, 1H), 6.49(d, J=9.4 Hz, 1H), 5.19 (bs, 1H), 4.33 (bs, 1H), 4.26 (t, J=8.3 Hz, 1H),4.16 (d, J=9.1 Hz, 1H), 3.69-3.51 (m, 2H), 2.19-1.82 (m, 2H), 1.38 (s,9H), 0.94 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆): δ 173.76, 170.41, 155.77,78.56, 69.28, 58.64, 58.17, 56.49, 37.75, 35.83, 28.64 (3C), 26.67 (3C).

Tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(AQ)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.Under nitrogen atmosphere, to a stirred solution of(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (AP)(1.40 g, 4.06 mmol),(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (AM)(1.04 g, 4.06 mmol), and DIPEA (2.12 mL, 1.57 g, 12.19 mmol) in dry THE(20 mL) was added HATU (1.85 g, 4.88 mmol) at 0° C. The resultingmixture was allowed to warm to rt and stirred for 5 h. The organicsolvent was removed under vacuo. Water (15 mL) was added to the residue,and the resulting mixture was stirred for 1 h and then was filtered. Thesolid was collected, dried in an oven at 50° C., and purified by flashcolumn chromatography on SiO₂ (DCM/Acetone, 75:25) to give the titledproduct as a white solid (1.57 g, 71% yield). ¹H NMR (400 MHz, CDCl₃): δ8.70 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.45-7.37 (m, 4H), 5.23 (d, J=8.8Hz, 1H), 5.14-5.02 (m, 1H), 4.82 (t, J=7.9 Hz, 1H), 4.53 (s, 1H), 4.22(d, J=9.0 Hz, 1H), 4.17 (d, J=11.1 Hz, 1H), 3.58 (d, J=8.6 Hz, 1H), 2.83(bs, 1H), 2.70-2.59 (m, 1H), 2.55 (s, 3H), 2.14-2.01 (m, 1H), 1.48 (d,J=7.0 Hz, 3H), 1.44 (s, 9H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ173.04, 169.45, 156.57, 150.29, 148.52, 143.14, 131.60, 130.91, 129.60(2C), 126.43 (2C), 80.57, 70.09, 59.01, 58.10, 56.43, 48.89, 35.07,34.68, 28.30 (3C), 26.47 (3C), 22.30, 16.10.

(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3)

The titled compound can be prepared according to the process describedby Raina K. et al. Proc. Nat. Acad. Sci. U.S.A. 2016, 113, 7124-7129. Asolution of 4N HCl in dioxane (6.0 mL) was added to tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(AQ)(1.55 g, 2.85 mmol) and the mixture was stirred at rt for 3 h. Thesolvent was evaporated to dryness and the crude residue was trituratedwith DEE, filtered off, and dried in an oven at 50° C. to give thetitled compound as a white solid (1.36 g, 99% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 9.11 (s, 1H), 8.62 (d, J=7.8 Hz, 1H), 8.16 (s, 3H),7.50-7.34 (m, 4H), 6.83 (s, 1H), 4.91 (q, J=7.2 Hz, 1H), 4.55 (t, J=8.4Hz, 1H), 4.31 (s, 1H), 3.89 (d, J=5.3 Hz, 1H), 3.75 (d, J=10.8 Hz, 1H),3.50 (dd, J=3.7, 10.9 Hz, 1H), 2.47 (s, 3H), 2.21-1.65 (m, 2H), 1.38 (d,J=7.0 Hz, 3H), 1.03 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆): δ 170.68,167.08, 151.52, 147.47, 145.31, 131.96, 129.84, 129.32 (2C), 126.85(2C), 69.35, 59.30, 58.51, 56.94, 48.24, 38.39, 34.85, 26.53 (3C),22.97, 16.14.

Tert-butyl(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamate(AR)

General Procedure III (1 h) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0.20 g, 0.416 mmol),4-((tert-butoxycarbonyl)amino)butanoic acid (0.093 g, 0.458 mmol), DIPEA(0.29 mL, 1.666 mmol), and HATU (0.198 g, 0.521 mmol) in dry DMF (1.0mL) to afford the titled compound as white solid (0.16 g, 61% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH,99:1 to 96:4). ¹H NMR (400 MHz, CDCl₃): δ 8.68 (s, 1H), 7.61 (d, J=7.3Hz, 1H), 7.44-7.34 (m, 4H), 7.23 (d, J=7.0 Hz, 1H), 5.18-5.04 (m, 1H),4.94 (s, 1H), 4.75 (t, J=8.1 Hz, 1H), 4.55-4.41 (m, 2H), 4.22-4.05 (m,1H), 3.69-3.55 (m, 1H), 3.25-3.04 (m, 2H), 2.53 (s, 3H), 2.46-2.34 (m,1H), 2.33-2.06 (m, 3H), 1.85-1.65 (m, 2H), 1.49 (d, J=6.9 Hz, 3H), 1.43(s, 9H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.76, 172.06,170.01, 156.76, 150.31, 148.44, 143.38, 131.62, 130.78, 129.51 (2C),126.46 (2C), 79.62, 70.13, 58.64, 58.54, 56.74, 48.80, 39.40, 36.00,34.74, 32.96, 28.40 (3C), 26.66, 26.56 (3C), 22.20, 16.08.

Tert-butyl(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)carbamate(AS)

General Procedure III (2 h) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (1.48 g, 3.08 mmol),5-((tert-butoxycarbonyl)amino)pentanoic acid (0.735 g, 3.38 mmol), DIPEA(2.14 mL, 12.31 mmol), and HATU (1.46 g, 3.85 mmol) in dry DMF (6.0 mL)to afford the titled compound as white solid (1.60 g, 81% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH,98:2 to 95:5). ¹H NMR (400 MHz, CDCl₃): δ 8.69 (s, 1H), 7.51 (d, J=7.0Hz, 1H), 7.41 (q, J=8.5 Hz, 4H), 6.31 (d, J=7.6 Hz, 1H), 5.18-5.04 (m,1H), 4.76 (t, J=7.9 Hz, 2H), 4.58 (d, J=8.6 Hz, 1H), 4.53 (bs, 1H), 4.13(d, J=11.4 Hz, 1H), 3.62 (d, J=10.4 Hz, 1H), 3.41 (bs, 1H), 3.18-3.00(m, 2H), 2.55 (s, 4H), 2.33-2.04 (m, 3H), 1.72-1.57 (m, 2H), 1.55-1.38(m, 14H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.59, 172.15,169.63, 156.14, 150.28, 148.49, 143.15, 131.58, 130.88, 129.55 (2C),126.45 (2C), 79.26, 70.06, 58.41, 57.69, 56.77, 48.84, 39.99, 35.73,35.46, 34.95, 29.36, 28.44 (3C), 26.52 (3C), 22.59, 22.26, 16.10.

Tert-butyl(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamate(AT)

General Procedure III (1 h) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0. 250 g, 0.521 mmol),6-((tert-butoxycarbonyl)amino)hexanoic acid (0.132 g, 0.573 mmol), DIPEA(0.36 mL, 2.083 mmol), and HATU (0.247 g, 0.651 mmol) in dry DMF (1.0mL) to afford the titled compound as white solid (0.213 g, 63% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH,95:5). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.49 (d, J=6.6 Hz, 1H),7.46-7.36 (m, 4H), 6.16 (d, J=8.3 Hz, 1H), 5.16-5.06 (m, 1H), 4.78 (t,J=8.1 Hz, 1H), 4.70 (bs, 1H), 4.58 (d, J=9.1 Hz, 1H), 4.53 (s, 1H), 4.17(d, J=11.6 Hz, 1H), 3.79-3.56 (m, 1H), 3.29-2.99 (m, 3H), 2.55 (s, 3H),2.31-2.05 (m, 3H), 1.56-1.40 (m, 16H), 1.37-1.24 (m, 2H), 1.07 (s, 9H).

Tert-butyl(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamate(AU)

General Procedure III (30 min) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0.250 g, 0.521 mmol),7-((tert-butoxycarbonyl)amino)heptanoic acid (0.14 g, 0.573 mmol), DIPEA(0.36 mL, 2.083 mmol), and HATU (0.247 g, 0.651 mmol) in dry DMF (1.0mL) to afford the titled compound as white solid (0.244 g, 68% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH,95:5). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.50 (d, J=6.2 Hz, 1H),7.41 (q, J=8.3 Hz, 4H), 6.18 (d, J=8.5 Hz, 1H), 5.17-5.05 (m, 1H), 4.77(t, J=8.0 Hz, 1H), 4.67-4.47 (m, 3H), 4.17 (d, J=11.5 Hz, 1H), 3.61 (d,J=10.6 Hz, 1H), 3.18-3.01 (m, 3H), 2.55 (s, 4H), 2.35-2.03 (m, 3H),1.74-1.57 (m, 4H), 1.55-1.40 (m, 12H), 1.32 (s, 4H), 1.07 (s, 9H); ¹³CNMR (101 MHz, CDCl₃): δ 173.9 (2C), 172.2, 169.6, 150.3, 148.4, 143.2,130.8, 129.6 (2C), 126.5 (2C), 109.6, 79.2, 70.0, 58.3, 57.6, 56.7,48.8, 40.3, 36.2, 35.3, 34.8, 29.7, 28.4 (3C), 28.4, 26.5 (3C), 26.2,25.3, 22.2, 16.0.

Tert-butyl(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(AW)

General Procedure III (1 h) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0.10 g, 0.208 mmol), tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (0.06 g, 0.229 mmol), DIPEA(0.14 ml, 0.833 mmol), and HATU (0.099 g, 0.260 mmol) in dry DMF (0.5mL) to afford the titled compound as white solid (0.072 g, 50% yield)following purification by flash column chromatography on SiO₂ (DCM/MeOH,97:3 to 95:5). ¹H NMR (400 MHz, CDCl₃): δ 8.69 (s, 1H), 7.52 (d, J=8.6Hz, 1H), 7.40 (d, J=7.3 Hz, 4H), 5.94 (s, 1H), 5.21-5.06 (m, 1H), 4.66(dd, J=35.2, 26.9 Hz, 3H), 4.22-3.05 (m, 14H), 2.54 (s, 3H), 2.37-2.01(m, 2H), 1.54-1.37 (m, 12H), 1.06 (s, 9H).

(2S,4R)-1-((S)-2-(4-Aminobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (AY)

General Procedure II (2 h) was followed by using tert-butyl(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamate(AR) (0.120 g, 0.190 mmol) and 4N HCl in dioxane (1.2 mL) to afford thetitled compound as light-yellow solid (0.10 g, 92% yield). ¹H NMR (400MHz, MeOD): δ 9.84 (s, 1H), 7.55 (dd, J=16.3, 8.3 Hz, 4H), 5.04 (q,J=7.0 Hz, 1H), 4.63-4.53 (m, 2H), 4.46 (s, 1H), 3.95-3.88 (m, 1H),3.79-3.71 (m, 1H), 2.99 (t, J=7.3 Hz, 2H), 2.61 (s, 3H), 2.52-2.43 (m,2H), 2.24 (dd, J=13.0, 7.6 Hz, 1H), 2.01-1.89 (m, 3H), 1.53 (d, J=7.0Hz, 3H), 1.07 (s, J=7.3 Hz, 9H).

(2S,4R)-1-((S)-2-(5-Aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (AZ)

General Procedure II (2 h) was followed by using tert-butyl(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)carbamate(AS)(1.35 g, 2.09 mmol) and 4N HCl in dioxane (10.0 mL) to afford thetitled compound as white solid (1.11 g, 91% yield). ¹H NMR (400 MHz,CD₃OD): δ 10.03 (s, 1H), 7.57 (d, J=8.3 Hz, 4H), 5.10-5.01 (m, 1H),4.73-4.56 (m, 2H), 4.46 (s, 1H), 3.91 (d, J=10.5 Hz, 1H), 3.76 (d,J=10.5 Hz, 1H), 3.33 (s, 1H), 3.02-2.84 (m, 2H), 2.64 (s, 3H), 2.48-2.33(m, 2H), 2.33-2.23 (m, 1H), 2.00-1.90 (m, 1H), 1.80-1.68 (m, 4H), 1.53(d, J=6.6 Hz, 3H), 1.05 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆): δ 172.12,171.08, 169.96, 152.39, 147.48, 145.34, 131.97, 129.80, 129.29 (2C),126.88 (2C), 69.19, 59.01, 56.88, 56.73, 48.17, 38.90, 38.20, 35.69,34.70, 27.09, 26.94 (3C), 22.91, 22.80, 16.13.

(2S,4R)-1-((S)-2-(6-Aminohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BA)

General Procedure II (1 h) was followed by using tert-butyl(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamate(AT)(0.20 g, 0.304 mmol) and 4N HCl in dioxane (2.0 mL) to afford thetitled compound as white solid (0.128 g, 71% yield). ¹H NMR (400 MHz,MeOD): δ 10.06 (s, 1H), 7.57 (dd, J=16.4, 7.8 Hz, 4H), 5.08-5.02 (m,1H), 4.67-4.56 (m, 2H), 4.46 (s, 1H), 3.90 (d, J=10.8 Hz, 1H), 3.81-3.72(m, 1H), 2.95 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 2.46-2.20 (m, 3H),2.02-1.89 (m, 1H), 1.75-1.63 (m, 4H), 1.54 (d, J=6.9 Hz, 3H), 1.41 (t,J=6.8 Hz, 2H), 1.07 (s, 9H).

(2S,4R)-1-((S)-2-(7-Aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BB)

General Procedure II (1 h) was followed by using tert-butyl(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamate(AU) (0.22 g, 0.327 mmol) and 4N HCl in dioxane (2.0 mL) to afford thetitled compound as white solid (0.199 g, 100% yield). ¹H NMR (400 MHz,MeOD): δ9.82 (s, 1H), 7.74-7.26 (m, 4H), 5.04 (q, J=7.0 Hz, 1H), 4.64(s, 1H), 4.60 (t, J=8.4 Hz, 1H), 4.46 (s, 1H), 3.90 (d, J=11.3 Hz, 1H),3.84-3.71 (m, 1H), 2.94 (t, J=7.5 Hz, 2H), 2.61 (s, 3H), 2.37-2.21 (m,3H), 2.05-1.92 (m, 1H), 1.79-1.62 (m, 4H), 1.54 (d, J=7.0 Hz, 3H),1.50-1.33 (m, 4H), 1.06 (s, 9H); ¹³C NMR (101 MHz, MeOD): δ 175.86,173.28, 172.25, 155.50, 147.60, 143.50, 136.81, 130.62 (2C), 128.52,128.10 (2C), 70.96, 68.11, 60.53, 59.04, 57.98, 49.63, 40.64, 38.82,36.44, 36.32, 29.58, 28.31, 27.03 (3C), 26.58, 22.40, 13.48.

(2S,4R)-1-((S)-2-(2-(3-Aminopropoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BC)

General Procedure III (30 min) was followed by using(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0.250 g, 0.521 mmol),2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (0.134 g, 0.573mmol), DIPEA (0.36 mL, 2.083 mmol), and HATU (0.247 g, 0.651 mmol) indry DMF (1.0 mL) to afford tert-butyl(3-(2-(((S)-1-(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)propyl)carbamate(AV) as white solid (0.215 g, 63% yield) after purification by flashcolumn chromatography on SiO₂ (DCM/MeOH, 95:5). Then, following generalProcedure II (1 h) by using tert-butyl(3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)propyl)carbamate(AV) (0.210 g, 0.318 mmol) and 4N HCl in dioxane (2.0 mL) the titledcompound was obtained as white solid (0.196 g, 100% yield). ¹H NMR (400MHz, MeOD): δ 9.88 (s, 1H), 7.55 (q, J=8.4 Hz, 4H), 5.04 (q, J=6.9 Hz,1H), 4.75-4.67 (m, 1H), 4.65-4.53 (m, 1H), 4.47 (s, 1H), 4.10 (d, J=3.6Hz, 2H), 3.90 (d, J=10.9 Hz, 1H), 3.80-3.70 (m, 2H), 3.37 (s, 2H), 3.13(t, J=6.6 Hz, 2H), 2.62 (s, 3H), 2.33-2.17 (m, 1H), 2.08-1.88 (m, 3H),1.54 (d, J=7.1 Hz, 3H), 1.40 (dd, J=4.3, 6.7 Hz, 2H), 1.07 (d, J=6.9 Hz,9H); ¹³C NMR (101 MHz, MeOD): δ 173.2, 172.4, 171.9, 156.4, 147.7,143.1, 137.1, 130.6 (2C), 128.3, 128.1 (2C), 71.0, 70.4, 60.6, 58.6,58.1, 50.2, 49.0, 39.4, 38.9, 36.8, 28.2, 26.9 (3C), 22.4, 13.3.

(2S,4R)-1-((S)-2-(2-(2-(2-Aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BD)

General Procedure II (2 h) was followed by using tert-butyl(2(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(AW)(0.06 g, 0.087 mmol) and 4N HCl in dioxane (1.0 mL) to afford thetitled compound as white solid (0.054 g, 100% yield). ¹H NMR (400 MHz,MeOD): δ 9.76 (s, 1H), 7.54 (q, J=8.1 Hz, 4H), 5.10-5.00 (m, 1H), 4.75(s, 1H), 4.66-4.53 (m, 1H), 4.46 (s, 1H), 4.20-3.96 (m, 2H), 3.88 (d,J=11.1 Hz, 1H), 3.82-3.72 (m, 8H), 3.27-3.16 (m, 2H), 2.60 (s, 3H),2.34-2.23 (m, 1H), 2.00-1.87 (m, 1H), 1.55 (d, J=7.1 Hz, 3H), 1.11-1.01(m, 9H).

(2S,4R)-1-((S)-2-(4-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 15)

General Procedure III (3 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.035 g, 0.089 mmol),(2S,4R)-1-((S)-2-(4-aminobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (AY) (0.05 g, 0.089 mmol), DIPEA (0.062 mL, 0.356 mmol),and HATU (0.042 g, 0.111 mmol) in dry DMF (0.6 mL) to afford the titledcompound as white solid (0.046 g, 60% yield) following purification byflash column chromatography on SiO₂(DCM/MeOH, 98:2 to 95:5). ¹H NMR (400MHz, CDCl₃): δ 8.69 (s, 1H), 7.62-7.55 (m, 1H), 7.49 (d, J=7.8 Hz, 1H),7.40 (q, J=8.3 Hz, 4H), 7.27-7.24 (m, 1H), 7.01 (dd, J=16.6, 9.0 Hz,1H), 6.95-6.89 (m, 2H), 5.16-5.02 (m, 1H), 4.78 (t, J=8.1 Hz, 1H), 4.61(s, 2H), 4.53 (d, J=8.2 Hz, 1H), 4.47 (s, 1H), 4.15 (d, J=11.6 Hz, 1H),3.92-3.79 (m, 4H), 3.63-3.40 (m, 8H), 3.36-3.24 (m, 1H), 2.63-2.51 (m,4H), 2.33-2.17 (m, 2H), 2.12-2.03 (m, 1H), 1.89-1.77 (m, 1H), 1.48 (d,J=7.0 Hz, 3H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.03, 172.34,170.98, 169.59, 168.90, 150.73 (dd, J=251.3, 11.4 Hz), 150.28, 148.51,146-73-146.38 (m), 144. 58 (dd, J=8.9, 1.6 Hz,), 144.21 (dd, J=247.3,14.1 Hz,), 143.17, 131.61, 130.87, 129.57 (2C), 126.46 (2C), 125.34 (d,J=3.4 Hz,), 124.52 (dd, J=7.7, 3.8 Hz), 112.54 (d, J=17.1 Hz), 106.25,72.36 (d, J=5.2 Hz), 70.11, 66.11 (2C), 58.25, 58.09, 56.75, 48.85,48.55 (2C), 37.82, 35.35, 34.80, 32.93, 26.54 (3C), 25.89, 22.22, 16.10.HRMS (ESI) m/z [M+H]+ calcd for C₄₂H₅₁F₂N₇O₇S₂ 868.33322. found868.3327.

(2S,4R)-1-((S)-2-(5-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 16)

General Procedure III (4 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.67 g, 1.71 mmol),(2S,4R)-1-((S)-2(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2carboxamide hydrochloride (AZ)(0.99 g, 1.71 mmol), DIPEA (1.19 mL, 6.82mmol), and HATU (0.81 g, 2.13 mmol) in dry DMF (7.5 mL) to afford thetitled compound as white solid (0.604 g, 40% yield) followingpurification by flash column chromatography on SiO₂(DCM/Acetone/MeOH,60:37:3). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.60 (ddd, J=8.5,6.0, 2.1 Hz, 1H), 7.48-7.34 (m, 5H), 7.12 (t, J=5.6 Hz, 1H), 7.05-6.92(m, 2H), 6.32 (d, J=8.6 Hz, 1H), 5.15-5.05 (m, 1H), 4.75 (t, J=8.0 Hz,1H), 4.66-4.53 (m, 3H), 4.49 (bs, 1H), 4.11 (d, J=11.4 Hz, 1H),3.90-3.80 (m, 4H), 3.59 (dd, J=11.4, 3.5 Hz, 1H), 3.55-3.46 (m, 4H),3.45-3.17 (m, 3H), 2.61-2.50 (m, 4H), 2.39-2.21 (m, 2H), 2.07 (dd,J=13.6, 8.3 Hz, 1H), 1.83-1.52 (m, 4H), 1.48 (d, J=6.9 Hz, 3H), 1.06 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.34, 172.25, 170.85, 169.54, 168.31,150.64 (dd, J=251.3, 11.3 Hz), 150.26, 148.50, 146.40 (d, J=1.7 Hz),144.69-144.42 (m), 144.19 (dd, J=247.5, 14.0 Hz), 143.11, 131.58,130.88, 129.56 (2C), 126.41 (2C), 125.32 (d, J=3.4 Hz), 124.48 (dd,J=7.7, 3.9 Hz), 112.49 (d, J=17.1 Hz), 106.25, 72.29 (d, J=5.0 Hz),70.03, 66.13 (2C), 58.24, 57.67, 56.72, 48.86, 48.55 (2C), 38.35, 35.47,35.35, 34.92, 28.73, 26.51 (3C), 22.40, 22.24, 16.10. HRMS (ESI) m/z[M+H]+ calcd for C₄₃H₅₃F₂N₇O₇S₂ 882.34887. found 882.3458.

(2S,4R)-1-((S)-2-(6-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexanamido)-3,3-dimethylbutanoyl-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 17)

General Procedure III (1.5 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.036 g, 0.102 mmol),(2S,4R)-1-((S)-2-(6-aminohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BA) (0.061 g, 0.102 mmol), DIPEA (0.07 mL, 0.407 mmol),and HATU (0.048 g, 0.127 mmol) in dry DMF (0.5 mL) to afford the titledcompound as white solid (0.024 g, 26% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 98:2 to 96:4). ¹H NMR(400 MHz, CDCl₃): δ 8.69 (s, 1H), 7.60 (ddd, J=8.6, 6.0, 2.3 Hz, 1H),7.50-7.34 (m, 5H), 7.08-6.97 (m, 2H), 6.95 (s, 1H), 6.16 (d, J=8.6 Hz,1H), 5.10 (p, J=7.3 Hz, 1H), 4.76 (t, J=8.0 Hz, 1H), 4.61-4.54 (m, 3H),4.51 (s, 1H), 4.12 (d, J=11.6 Hz, 1H), 3.89-3.81 (m, 4H), 3.58 (dd,J=11.4, 3.5 Hz, 1H), 3.55-3.50 (m, 4H), 3.32 (dd, J=14.2, 7.1 Hz, 2H),3.22-3.12 (m, 1H), 2.61-2.50 (m, 4H), 2.31-2.16 (m, 2H), 2.14-2.04 (m,1H), 1.69-1.59 (m, 2H), 1.57-1.46 (m, 5H), 1.39-1.26 (m, 2H), 1.06 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.50, 172.22, 170.85, 169.57, 169.47,168.04, 150.67 (dd, J=251.3, 11.4 Hz), 150.26, 148.51, 146.52 (dd,J=6.4, 1.7 Hz), 144.18 (dd, J=246.8, 14.7 Hz), 143.13, 131.57, 130.90,129.57 (2C), 126.42 (2C), 125.31 (d, J=3.6 Hz), 124.49 (dd, J=7.7, 3.8Hz), 112.46 (d, J=17.1 Hz), 106.16, 72.37 (d, J=5.2 Hz), 70.01, 66.13(2C), 58.27, 57.58, 56.71, 48.86, 48.54 (2C), 38.87, 36.15, 35.41,34.87, 29.20, 26.50 (3C), 26.18, 25.07, 22.25, 16.11. HRMS (ESI) m/z[M+H]+ calcd for C₄₄H₅₅F₂N₇O₇S₂ 896.36452. found 896.3645.

(2S,4R)-1-((S)-2-(7-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 18)

General Procedure III (1 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.036 g, 0.100 mmol),(2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BB) (0.061 g, 0.100 mmol), DIPEA (0.069 mL, 0.401 mmol),and HATU (0.048 g, 0.127 mmol) in dry DMF (0.5 mL) to afford the titledcompound as white solid (0.045 g, 49% yield) following purification byflash column chromatography on SiO₂(DCM/Acetone/MeOH, 60:40:1.5). ¹H NMR(400 MHz, CDCl₃): δ 8.68 (s, 1H), 7.60 (ddd, J=2.2, 6.0, 8.6 Hz, 1H),7.52 (d, J=7.9 Hz, 1H), 7.47-7.34 (m, 4H), 7.10-6.81 (m, 3H), 6.28 (d,J=8.8 Hz, 1H), 5.09 (p, J=7.1 Hz, 1H), 4.73 (t, J=7.9 Hz, 1H), 4.59 (d,J=8.8 Hz, 1H), 4.56 (s, 2H), 4.50 (s, 1H), 4.07 (d, J=11.4 Hz, 1H),3.89-3.80 (m, 4H), 3.76-3.66 (m, 1H), 3.61 (dd, J=3.6, 11.3 Hz, 1H),3.54-3.47 (m, 4H), 3.30 (q, J=5.9 Hz, 2H), 2.53 (s, 3H), 2.50-2.40 (m,1H), 2.32-2.01 (m, 3H), 1.69-1.49 (m, 4H), 1.48 (d, J=6.9 Hz, 3H),1.38-1.28 (m, 4H), 1.05 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.50,171.99, 170.78, 169.83, 167.99, 150.62 (dd, J=11.5, 251.1 Hz), 150.30,148.45, 146.93-146.03 (m), 144.57 (dd, J=1.5, 9.1 Hz), 144.16 (dd,J=14.0, 247.2 Hz), 143.24, 131.58, 130.83, 129.52 (2C), 126.43 (2C),125.28 (d, J=3.4 Hz), 124.48 (dd, J=4.0, 7.7 Hz), 114.06, 112.43 (d,J=17.1 Hz), 106.14, 72.34 (d, J=5.1 Hz), 69.90, 66.12, 58.48, 57.46,56.74, 53.85, 48.80, 48.52, 38.89, 36.19, 35.69, 35.12, 29.15, 28.44,26.51 (3C), 26.31, 25.34, 22.24, 16.09. HRMS (ESI) m/z [M+H]+ calcd forC₄₅H₅₇F₂N₇O₇S₂ 910.38017. found 910.3802.

(2S,4R)-1-((S)-2-(2-(3-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 19)

General Procedure III (1 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.035 g, 0.098 mmol),(2S,4R)-1-((S)-2-(2-(3-aminopropoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BC) (0.059 g, 0.098 mmol), DIPEA (0.069 mL, 0.395 mmol),and HATU (0.048 g, 0.127 mmol) in dry DMF (0.5 mL) to afford the titledcompound as white solid (0.09 g, 53% yield) following purification byflash column chromatography on SiO₂(DCM/MeOH, 95:5). ¹H NMR (400 MHz,CDCl₃): δ 8.68 (s, 1H), 7.61 (ddd, J=2.2, 6.0, 8.7 Hz, 1H), 7.45-7.32(m, 5H), 7.25 (t, J=5.9 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.03-6.96 (m,1H), 6.96 (s, 1H), 5.07 (p, J=7.0 Hz, 1H), 4.71 (t, J=7.7 Hz, 1H),4.63-4.53 (m, 3H), 4.50 (s, 1H), 4.04-3.87 (m, 3H), 3.86-3.78 (m, 4H),3.67-3.53 (m, 4H), 3.53-3.48 (m, 4H), 3.46 (q, J=6.4 Hz, 2H), 2.53 (s,3H), 2.54-2.45 (m, 1H), 2.12-1.98 (m, 1H), 1.87 (p, J=6.5 Hz, 2H), 1.47(d, J=6.9 Hz, 3H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 171.45,170.78, 169.97, 169.69, 168.21, 150.61 (dd, J=251.3, 11.4 Hz), 150.32,148.47, 146.40-146.32 (m), 144.56 (dd, J=9.1, 1.4 Hz), 144.22 (dd,J=247.1, 14.0 Hz), 143.16, 131.60, 130.85, 129.54 (2C), 126.43 (2C),125.35 (d, J=3.4 Hz), 124.53 (dd, J=7.7, 4.0 Hz), 112.56 (d, J=17.0 Hz),106.19, 72.34 (d, J=4.9 Hz), 70.12, 70.03, 69.21, 66.11 (2C), 58.42,56.96, 56.61, 48.87, 48.54 (2C), 36.18, 35.54, 35.36, 29.45, 26.47 (3C),22.22, 16.09. HRMS (ESI) m/z [M+H]+ calcd for C₄₃H₅₃F₂N₇O₈S₂ 898.34379.found 898.3438.

(2S,4R)-1-((S)-2-(tert-butyl)-14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-4,13-dioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 20)

General Procedure III (3 h) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.026 g, 0.072 mmol),(2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (BD) (0.045 g, 0.072 mmol), DIPEA (0.05 mL, 0.287 mmol),and HATU (0.034 g, 0.089 mmol) in dry DMF (0.6 mL) to afford the titledcompound as white solid (0.038 g, 57% yield) following purification byflash column chromatography on SiO₂(DCM/MeOH, 97:3 to 95:5). ¹H NMR (400MHz, CDCl₃): δ 8.70 (s, 1H), 7.79-7.67 (m, 2H), 7.42 (dt, J=24.5, 8.6Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.07-6.92 (m, 2H), 5.09 (p, J=7.2 Hz,1H), 4.66-4.53 (m, 4H), 4.49 (s, 1H), 4.10-3.92 (m, 3H), 3.89-3.80 (m,4H), 3.80-3.55 (m, 9H), 3.54-3.45 (m, 4H), 2.90 (s, 1H), 2.55 (s, 3H),2.50-2.38 (m, 1H), 1.98-1.86 (m, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.06 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 171.35, 170.59, 170.29, 169.63, 168.34,150.47 (dd, J=251.0, 11.4 Hz), 150.31, 148.55, 145.91-145.78 (m), 144.43(d, J=8.4 Hz), 14426 (dd, J=246.8, 14.0 Hz), 143.00, 131.56, 130.98,129.60 (2C), 126.46 (2C), 125.25 (d, J=3.5 Hz), 124.64-124.40 (m),112.63 (d, J=17.0 Hz), 106.39, 72.29 (d, J=4.6 Hz), 71.31, 70.44, 70.35,70.10, 70.08, 66.14 (2C), 58.44, 56.91, 56.72, 48.86, 48.53 (2C), 39.18,35.75, 35.57, 26.52 (3C), 21.98, 16.12. HRMS (ESI) m/z [M+H]+ calcd forC₄₄H₅₅F₂N₇O₉S₂ 928.35435. found 928.3540.

Ethyl 8-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanoate (BE)

To the solution of 2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol(ARB-1) (0.1 g, 0.335 mmol) in ACN (3.0 mL) K₂CO₃ (0.115 g, 0.834 mmol)and ethyl 8-bromooctanoate (commercially available from, for example,Fluorochem) (0.084 g, 0.335 mmol) were added and the mixture was stirredat rt overnight. Then, the solvent was evaporated under vacuo and thecrude residue diluted with water (10 mL) and extracted with EA (5 mL×3).The reunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and concentrated under reduced pressure to afford a yellow oilwhich was purified by flash column chromatography on SiO₂ (PE/EA, 95:5to 8:2) affording the titled compound as white solid (0.135 g, 86%yield). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (ddd, J=8.8, 6.3, 2.3 Hz, 1H),7.25 (s, 1H), 6.90 (td, J=9.2, 7.4 Hz, 1H), 2.29 (t, J=7.5 Hz, 2H),1.84-1.74 (m, 2H), 1.63 (dd, J=14.6, 7.3 Hz, 2H), 1.51-1.31 (m, 6H),1.25 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 173.80, 169.86,150.52 (dd, J=249.4, 11.7 Hz), 146.11-146.03 (m), 144.50 (d, J=2.7 Hz),144.65 (dd, J=246.3, 13.7 Hz), 125.11-125.01 (m), 123.80 (dd, J=8.0, 4.0Hz), 111.12 (d, J=17.1 Hz), 106.34, 74.12 (d, J=5.6 Hz), 66.22 (2C),60.20, 48.57 (2C), 34.33, 30.21, 29.04, 28.96, 25.67 (2C), 24.89, 14.27.HRMS (ESI) m/z [M+Na]+ calcd for C₄₄H₅₆F₂N₆O₆S₂ 889.35630. found889.35713.

8-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanoic acid (BF)

To the solution of ethyl8-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanoate (BE)(0.095 g, 0.203 mmol) in EtOH (1.0 mL) was added 1M NaOH solution (1.0mL, 1.014 mmol) and the mixture was stirred at reflux for 4 h. Aftercooling, the mixture was poured in ice-water, the pH was slowly adjustedto 2 with 2N HCl and the reaction mixture was extracted with EA (05mL×3). The combined organic layers were washed with brine (10 mL×2),dried over anhydrous Na₂SO₄, and concentrated under reduced pressureyielding the titled compound as a white solid (0.072 g, 81% yield). ¹HNMR (400 MHz, DMSO-d_(h)): δ 7.79 (ddd, J=8.9, 6.3, 2.4 Hz, 1H), 7.24(s, 1H), 6.90 (td, J=9.2, 7.4 Hz, 1H), 4.13-4.03 (m, 2H), 3.90-3.79 (m,4H), 3.58-3.46 (m, 4H), 2.35 (t, J=7.5 Hz, 2H), 1.85-1.72 (m, 2H),1.71-1.56 (m, 2H), 1.51-1.33 (m, 6H); ¹³C NMR (101 MHz, CDCl₃): δ178.64, 169.92, 150.54 (dd, J=249.5, 11.7 Hz), 146.15-146.02 (m),144.74, 144.67 (dd, J=246.4, 13.5 Hz), 125.09 (d, J=3.6 Hz), 123.82 (dd,J=7.9, 3.9 Hz), 111.14 (d, J=17.1 Hz), 106.38, 74.11 (d, J=5.6 Hz),66.22 (2C), 48.57 (2C), 33.78, 30.19, 28.94, 28.91, 25.65, 24.59.

(2S,4R)-1-((S)-2-(8-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 21)

Under nitrogen atmosphere, to a stirred solution of8-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanoic acid(BF)(0.018 g, 0.041 mmol),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (E3LB-3) (0.020 g, 0.041 mmol), and DIPEA (0.029 mL, 0.166mmol) in dry DMF (0.5 mL) was added HATU (0.0197 g, 0.051 mmol) and thestirring was continued at rt overnight. The reaction mixture was pouredin ice-water (10 mL) yielding a precipitate which was collected byfiltration, dried, and purified by flash column chromatography on SiO₂(DCM/MeOH, 97:3) to afford the titled compound as light-yellow solid(0.018 g, 51% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 7.85-7.77(m, 1H), 7.48-7.35 (m, 5H), 7.24 (s, 1H), 6.93 (dd, J=16.9, 8.4 Hz, 1H),6.13 (d, J=7.6 Hz, 1H), 5.14-5.04 (m, 1H), 4.76 (t, J=8.1 Hz, 1H),4.61-4.49 (m, 2H), 4.16 (d, J=11.8 Hz, 1H), 4.10 (t, J=6.1 Hz, 2H),3.94-3.79 (m, 4H), 3.64-3.51 (m, 1H), 2.56 (s, 4H), 2.23 (t, J=7.3 Hz,2H), 2.12-2.02 (m, 1H), 1.85-1.73 (m, 2H), 1.71-1.56 (m, 2H), 1.53-1.40(m, 5H), 1.35 (s, 4H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.88,172.27, 169.84, 169.55, 150.71 (dd, J=250.0, 11.9 Hz), 150.58, 149.22,147.60, 146.03 (dd, J=9.1, 1.0 Hz), 144.62 (dd, J=246.5, 13.5 Hz),143.53, 132.22, 130.29, 129.59 (2C), 126.55 (2C), 124.49-124.36 (m),124.22-123.95 (m), 111.21 (d, J=17.2 Hz), 106.15, 74.18 (d, J=5.6 Hz),70.02, 66.19 (2C), 58.30, 57.57, 48.88, 48.82 (2C), 36.41, 35.22, 34.82,30.14, 29.02, 28.90, 26.53 (3C), 25.62, 25.43, 22.26, 15.72. HRMS (ESI)m/z [M+Na]+ calcd for C₄₄H₅₆F₂N₆O₆S₂ 889.35685. found 889.35713.

(S)-3-((Tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoicacid (E3LB-4 (A))

The titled compound can be prepared according to the process describedby Han, X et al. J Med Chem. 2019, 62, 941-964. Under nitrogenatmosphere, a mixtureof(S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoic acid(0.25 g, 0.726 mmol), 4-methylthiazole (commercially available from, forexample, Fluorochem) (0.132 ml, 1.453 mmol), palladium (II) acetate(1.63 mg, 7.26×10⁻³ mmol), and potassium acetate (0.142 g, 1.453 mmol)in dry DMA (0.8 mL) was stirred at 90° C. for 18 h. After cooling, thereaction mixture was extracted with EA (15 mL×4). The combined organiclayers were washed with water (20 mL×3), brine (20 mL×2), dried overanhydrous Na₂SO₄, and concentrated under reduced pressure yielding anoil which was purified by flash column chromatography on SiO₂ (DCM/MeOH,98:2 to 97:3) to afford the titled compound as a white solid (0.072 g,81% yield). The solid was collected by filtration and dried in an ovenat 50° C. to afford the titled compound (0.070 g, 27% yield) as a graysolid. ¹H NMR (400 MHz, CDCl₃): a 8.72 (s, 1H), 7.38 (s, 4H), 5.65 (bs,1H), 5.16 (bs, 1H), 3.04-2.75 (m, 2H), 2.46 (s, 3H), 1.43 (s, 9H).

Methyl(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylatehydrochloride (BG)

The titled compound can be prepared according to the process describedby Laurent, A. et al. PCT Int. Appl. WO 2011098904. To the solution ofmethyl(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate(AO) (6.80 g, 18.971 mmol) in dry DCM (10.0 mL) at 0° C. a solution of4N HCl in dioxane (10.0 mL) was added. The mixture was stirred at rt for4 h. The solvent was evaporated to dryness and the crude residue wastriturated with DEE and filtered off to afford the titled compound as awhite solid (5.15 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (bs,3H), 4.42 (t, J=8.7 Hz, 1H), 4.36 (s, 1H), 3.94 (s, 1H), 3.81 (d, J=11.1Hz, 1H), 3.64 (s, 3H), 3.60-3.48 (m, 2H), 2.24-2.11 (m, 1H), 1.98-1.85(m, 1H), 1.03 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆): δ 172.30, 167.73,69.30, 58.41, 58.36, 56.64, 52.33, 37.71, 34.81, 26.40 (3C).

Methyl(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate(BH)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of 1-fluorocyclopropane-1-carboxylic acid (commerciallyavailable from, for example, Fluorochem) (0.60 g, 5.765 mmol), methyl(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylatehydrochloride (BG) (1.545 g, 5.241 mmol), and DIPEA (4.564 mL, 26.207mmol) in dry DMF (5.0 mL) was added HATU (2.391 g, 6.289 mmol). Stirringwas continued at rt overnight. The reaction mixture was diluted withwater (30 mL) and extracted with EA (20 mL×4). The reunited organiclayers were washed with water (30 mL×2), brine (30 mL), dried overanhydrous Na₂SO₄ and then evaporated under reduced pressure to give anoil residue, which was purified by double flash column chromatography onSiO₂ (first: DCM/MeOH, 98:2; second: DCM/Acetone, 95:5 to 8:2) affordingthe titled compound as white solid (0.687 g, 38% yield). ¹H NMR (400MHz, CDCl₃): δ 7.10 (d, J=5.9 Hz, 1H), 4.72-4.64 (m, 1H), 4.57 (d, J=9.1Hz, 1H), 4.53 (s, 1H), 4.02 (d, J=11.2 Hz, 1H), 3.79-3.69 (m, 4H),2.41-2.29 (m, 1H), 2.07-2.97 (m, 2H), 1.37-1.20 (m, 4H), 1.08 (s, 9H);¹³C NMR (101 MHz, CDCl₃): δ 172.54, 170.26, 170.02, 78.27 (d, J=205.7Hz), 70.39, 57.67, 57.34, 56.47, 52.26, 37.65, 35.75, 26.33 (3C), 13. 68(d, J=10.3 Hz).

(2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (E3LB-4(B))

To the solution of methyl(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate(BH)(0.65 g, 1.887 mmol) in THF (5.0 mL) at 0° C. was added the solutionof lithium hydroxide monohydrate (0.792 g, 18.874 mmol) in water (2.5mL). The resulting mixture was stirred at rt for 18 h. The organicsolvent was removed under vacuo, the residue was diluted with ice-water(15 mL) and the pH was slowly adjusted to 2-3 with 2N HCl. The mixturewas then extracted with EA (5 mL×4). The reunited organic layers werewashed with brine (10 mL), dried over anhydrous Na₂SO₄ and thenevaporated under reduced pressure to give a residue which was trituredwith DEE, filtered off, and dried to give the titled compound as a whitesolid (0.497 g, 80% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.55 (bs, 1H),7.27 (d, J=6.9 Hz, 1H), 5.21 (d, J=3.7 Hz, 1H), 4.60 (d, J=9.1 Hz, 1H),4.3-4.25 (m, 2H), 3.70-3.54 (m, 2H), 2.21-2.06 (m, 1H), 1.96-1.84 (m,1H), 1.44-1.10 (m, 4H), 0.96 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆): δ173.56, 169.56, 168.53 (d, J=20.3 Hz), 78.55 (d, J=232.5 Hz), 69.28,58.27, 56.88, 56.78, 37.69, 36.48, 26.57 (3C), 13.33 (dd, J=23.7, 10.3Hz).

Tert-butyl(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamate(BI)

To the solution of 2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol(ARB-1) (0.250 g, 0.838 mmol) in ACN (3.5 mL) K₂CO₃ (0.289 g, 2.095mmol) and tert-butyl (4-(2-chloroacetamido)butyl)carbamate (0.244 g,0.922 mmol) were added and the mixture was refluxed for 18 h. Then, thesolvent was evaporated under vacuo and the crude residue diluted withwater (15 mL) yielding a solid which was collected by filtration,tritured by DEE and filtered off to afford the titled compound as whitesolid (0.366 g, 83% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.63-7.57 (m,1H), 7.07 (s, 1H), 7.04-6.96 (m, 1H), 6.94 (s, 1H), 4.60 (s, 3H),3.91-3.81 (m, 4H), 3.59-3.49 (m, 4H), 3.36 (dd, J=12.6, 6.4 Hz, 2H),3.23-3.10 (m, 2H), 1.64-1.50 (m, 4H), 1.46 (s, 9H).

Tert-butyl(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamate(BJ)

To the solution of 2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenol(ARB-1) (0.06 g, 0.201 mmol) in ACN (1.0 mL) K₂CO₃ (0.069 g, 0.503 mmol)and tert-butyl (6-(2-chloroacetamido)hexyl)carbamate (0.065 g, 0.221mmol) were added and the mixture was refluxed for 18 h. Then, thesolvent was evaporated under vacuo and the crude residue diluted withwater (10 mL) yielding a solid which was collected by filtration,tritured by DEE and filtered off to afford the titled compound as whitesolid (0.078 g. 70% yield). ¹H NMR (400 MHz, CDC): δ 7.60 (t, J=7.5 Hz,1H), 7.06 (s, 1H), 7.00 (dd, J=16.6, 8.9 Hz, 1H), 6.94 (s, 1H), 4.60 (s,2H), 4.55 (s, 1H), 3.90-3.84 (m, 4H), 3.59-3.51 (m, 4H), 3.39-3.29 (m,2H), 3.18-3.08 (m, 2H), 1.59-1.48 (m, 4H), 1.46 (s, 9H), 1.40-1.31 (m,4H).

N-(4-Aminobutyl)-2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamidehydrochloride (BK)

To the solution of tert-butyl(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamate(BI) (0.093 g, 0.176 mmol) in dry dioxane (0.4 mL) at 0° C. a solutionof 4N HCl in dioxane (0.44 mL) was added. The mixture was stirred at rtfor 2 h. The solvent was evaporated to dryness and the crude residue wastriturated with DEE and filtered off to afford the titled compound as awhite solid (0.081 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆): δ8.42-8.34 (m, 1H), 8.03 (bs, 3H), 7.81 (t, J=7.2 Hz, 1H), 7.68 (s, 1H),7.25 (dd, J=17.3, 9.1 Hz, 1H), 4.61 (s, 2H), 3.80-3.68 (m, 4H),3.50-3.39 (m, 4H), 3.22-3.10 (m, 2H), 2.85-2.72 (m, 2H), 1.67-1.42 (m,4H); ¹³C NMR (101 MHz, DMSO-d₆): δ 170.01, 167.60, 150.10 (dd, J=247.8,11.3 Hz), 144.80 (d, J=8.6 Hz), 144.57-144.46 (m), 144.04 (dd, J=245.5,14.0 Hz), 124.89 (d, J=2.6 Hz), 124.67 (d, J=7.9 Hz), 112.25 (d, J=17.0Hz), 108.05, 72.08 (d, J=5.8 Hz), 65.83 (2C), 48.72 (2C), 38.83, 38.17,26.48, 24.83.

N-(6-Aminohexyl)-2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamidehydrochloride (BL)

To the solution of tert-butyl(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamate(BJ) (0.067 g, 0.121 mmol) in dry dioxane (0.3 mL) at 0° C. a solutionof 4N HCl in dioxane (0.3 mL) was added. The mixture was stirred at rtfor 2 h. The solvent was evaporated to dryness and the crude residue wastriturated with DEE and filtered off to afford the titled compound as alight-yellow solid (0.059 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆): δ8.30 (s, 1H), 7.96 (bs, 3H), 7.85-7.77 (m, 1H), 7.66 (s, 1H), 7.25 (dd,J=17.1, 9.4 Hz, 1H), 4.60 (s, 2H), 3.78-3.69 (m, 4H), 3.49-3.42 (m, 4H),3.19-3.09 (m, 2H), 2.8-2.70 (m, 2H), 1.59-1.49 (m, 2H), 1.49-1.38 (m,2H), 1.38-1.22 (m, 4H).

Tert-butyl(S)-(3-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate(BM)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of(S)-3-((tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoicacid (E3LB-4 (A)) (0.030 g, 0.083 mmol),N-(4-aminobutyl)-2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamidehydrochloride (BK) (0.038 g, 0.083 mmol), and DIPEA (0.072 mL, 0.414mmol) in dry DMF (1.0 mL) was added HATU (0.038 g, 0.099 mmol). Stirringwas continued at rt overnight. The reaction mixture was poured inice-water yielding a precipitate which was collected by filtration,dried, and purified by flash column chromatography on SiO₂, (DCM/MeOH,97:3) affording the titled compound as white solid (0.030 g, 48% yield).¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 7.58 (s, 1H), 7.45-7.35 (m,4H), 7.08 (bs, 1H), 7.00 (dd, J=17.2, 8.8 Hz, 1H), 6.91 (s, 1H), 6.35(bs, 1H), 6.17 (bs, 1H), 5.06 (bs, 1H), 4.60 (s, 2H), 3.91-3.81 (m, 4H),3.59-3.50 (m, 4H), 3.32-3.11 (m, 4H), 2.82-2.59 (m, 2H), 2.53 (s, 3H),1.59-1.33 (m, 13H).

Tert-butyl(S)-(3-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate(BN)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of(S)-3-((tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoicacid (E3LB-4 (A)) (0.043 g, 0.120 mmol),N-(6-aminohexyl)-2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamidehydrochloride (BL) (0.059 g, 0.120 mmol), and DIPEA (0.105 mL, 0.60mmol) in dry DMF (1.5 mL) was added HATU (0.055 g, 0.144 mmol). Stirringwas continued at rt overnight. The reaction mixture was poured inice-water and extracted with EA (10 mL×3). The reunited organic layerswere washed with water (10 mL×2), brine (10 mL), dried over anhydrousNa₂SO₄ and then evaporated under reduced pressure to give a cruderesidue which was purified by flash column chromatography on SiO₂(DCM/MeOH, 97:3 to 96:4) affording the titled compound as light-yellowsolid (0.061 g, 63% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H),7.62-7.55 (m, 1H), 7.44-7.35 (m, 4H), 7.11 (bs, 1H), 7.00 (dd, J=16.8,9.0 Hz, 1H), 6.92 (s, 1H), 6.43 (bs, 1H), 5.94 (bs, 1H), 5.06 (s, 1H),4.61 (s, 2H), 3.89-3.83 (m, 4H), 3.58-3.52 (m, 4H), 3.38-3.05 (m, 4H),2.81-2.61 (m, 2H), 2.55 (s, 3H), 1.54-1.34 (m, 13H), 1.31-1.25 (m, 4H).

(S)-3-Amino-N-(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)-3-(4-(4-methylthiazol-5-yl)phenyl)propanamidehydrochloride (BO)

To the solution of tert-butyl(S)-(3-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate(BM) (0.03 g, 0.039 mmol) in dry DCM (0.3 mL) at 0° C. a solution of 4NHCl in dioxane (0.4 mL) was added. The mixture was stirred at rtovernight. The solvent was evaporated to dryness and the crude residuewas triturated with DEE and filtered off to afford the titled compoundas white solid (0.027 g, 100% yield). ¹H NMR (400 MHz, MeOD): δ 9.71 (s,1H), 7.70 (s, 4H), 7.57-7.36 (m, 1H), 7.35-7.09 (m, 2H), 5.07 (s, 2H),4.82 (t, J=6.3 Hz, 1H), 4.00-3.86 (m, 4H), 3.86-3.71 (m, 4H), 3.28-3.08(m, 4H), 3.08-2.93 (m, 2H), 2.60 (s, 3H), 1.52-1.36 (m, 4H).

(S)-3-Amino-N-(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)-3-(4-(4-methylthiazol-5-yl)phenyl)propanamidehydrochloride (BP)

To the solution of tert-butyl(S)-(3-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate(BN)(0.05 g, 0.062 mmol) in dry DCM (0.5 mL) at 0° C. a solution of 4NHCl in dioxane (0.6 mL) was added. The mixture was stirred at rtovernight. The solvent was evaporated to dryness and the crude residuewas triturated with DEE and filtered off to afford the titled compoundas light-yellow solid (0.044 g, 100% yield). ¹H NMR (400 MHz, MeOD): δ9.97 (s, 1H), 7.78-7.66 (m, 4H), 7.48-7.38 (m, 1H), 7.28-7.13 (m, 2H),5.09 (s, 2H), 4.83 (t, J=6.9 Hz, 1H), 3.98-3.87 (m, 4H), 3.84-3.75 (m,4H), 3.23 (t, J=6.7 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 3.08-2.93 (m, 2H),2.64 (s, 3H), 1.55-1.37 (m, 4H), 1.33-1.17 (m, 4H).

(2S,4R)—N—((S)-3-((4-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide(Example 22)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (E3LB-4(B)) (0.013 g, 0.038 mmol),(S)-3-amino-N-(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)-3-(4-(4-methylthiazol-5-yl)phenyl)propanamidehydrochloride (BO) (0.027 g, 0.038 mmol), and DIPEA (0.033 mL, 0.191mmol) in dry DMF (0.5 mL) was added HATU (0.018 g, 0.048 mmol). Stirringwas continued at rt overnight. The reaction mixture was poured inice-water yielding a precipitate which was collected by filtration,dried, and purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5 to 93:7) affording the titled compound as white solid (0.004 g, 11%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 8.00 (d, J=7.8 Hz, 1H),7.62-7.56 (m, 1H), 7.43-7.34 (m, 4H), 7.15 (bs, 1H), 7.10 (dd, J=8.8,3.4 Hz, 1H), 6.99 (dd, J=16.7, 8.9 Hz, 1H), 6.93 (s, 1H), 6.73 (bs, 1H),5.35 (dd, J=13.3, 6.1 Hz, 1H), 4.67 (t, J=8.1 Hz, 1H), 4.62 (d, J=9.1Hz, 1H), 4.56 (d, J=4.0 Hz, 2H), 4.51 (s, 1H), 3.98 (d, J=11.2 Hz, 1H),3.88-3.82 (m, 4H), 3.74 (dd, J=11.0, 3.6 Hz, 1H), 3.55-3.47 (m, 4H),3.31-3.17 (m, 4H), 2.85-2.71 (m, 2H), 2.51 (s, 3H), 2.25-2.17 (m, 2H),1.55-1.42 (m, 4H), 1.39-1.22 (m, 5H), 1.06 (s, 9H); ¹³C NMR (101 MHz,CDCl₃): δ 170.81, 170.77, 170.73, 170.11, 170.02, 169.81, 168.47, 150.68(dd, J=251.3, 11.5 Hz), 150.34, 148.48, 146.19, 144.54 (d, J=9.0 Hz),144.14 (dd, J=247.1, 14.1 Hz), 140.45, 131.49, 131.09, 129.45 (2C),126.84 (2C), 125.11, 124.54 (dd, J=7.6, 3.9 Hz), 112.54 (d, J=17.1 Hz),106.17, 78.27 (d, J=232.3 Hz), 72.26 (d, J=4.9 Hz), 70.17, 66.09 (2C),59.41, 57.48, 56.76, 50.61, 48.58 (2C), 41.98, 39.10, 38.66, 37.22,35.84, 27.10, 26.47 (3C), 26.08, 16.10, 13.64 (dd, J=17.9, 10.2 Hz)(2C). HRMS (ESI) m/z [M+H]+ calcd for C₄₇H₅₇F₃N₈O₈S₂ 983.37656. found983.37691.

(2S,4R)—N—((S)-3-((6-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide(Example 23)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (E3LB-4(B)) (0.018 g, 0.054 mmol),(S)-3-amino-N-(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)-3-(4-(4-methylthiazol-5-yl)phenyl)propanamidehydrochloride (BP)(0.040 g, 0.054 mmol), and DIPEA (0.047 mL, 0.272mmol) in dry DMF (0.7 mL) was added HATU (0.026 g, 0.068 mmol). Stirringwas continued at rt overnight. The reaction mixture was poured inice-water yielding a precipitate which was collected by filtration,dried, and purified by flash column chromatography on SiO₂ (DCM/MeOH,96:4 to 94:6) affording the titled compound as white solid (0.024 g, 44%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.96 (d, J=8.1 Hz, 1H),7.58 (t, J=6.5 Hz, 1H), 7.40 (s, 4H), 7.16-7.05 (m, 2H), 7.00 (dd,J=16.6. 8.9 Hz, 1H), 6.92 (s, 1H), 6.38 (bs, 1H), 5.39-5.32 (m, 1H),4.69 (t, J=7.9 Hz, 1H), 4.66-4.57 (m, 3H), 4.54 (s, 1H), 4.01 (d, J=11.1Hz, 1H), 3.89-3.82 (m, 4H), 3.74 (dd, J=11.0, 3.6 Hz, 1H), 3.57-3.51 (m,4H), 3.32-3.24 (m, 2H), 3.23-3.14 (m, 2H), 2.87-2.71 (m, 2H), 2.53 (s,3H), 2.32-2.17 (m, 2H), 1.52-1.40 (m, 4H), 1.39-1.25 (m, 9H), 1.09 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 170.81, 170.74, 170.63, 170.01 (d,J=20.2 Hz), 169.95, 168.29, 150.86 (dd, J=251.6, 11.4 Hz), 150.36,148.39, 146.08-145.96 (m), 144.58 (d, J=8.9 Hz), 144.20 (dd, J=247.36,14.80 Hz), 140.55, 131.60, 131.02, 129.48 (2C), 126.82 (2C),124.96-124.77 (m), 124.55 (dd, J=7.8, 4.0 Hz), 112.49 (d, J=17.1 Hz),106.02, 78.32 (d, J=219.5 Hz), 7228 (d, J=5.2 Hz), 70.20, 66.08 (2C),59.33, 57.48, 56.67, 50.63, 48.63 (2C), 41.92, 39.06, 38.60, 37.08,35.68, 29.28, 29.05, 26.48 (3C), 25.88, 25.82, 16.07, 13.68 (dd, J=10.2,7.0 Hz)(2C). HRMS (ESI) m/z [M+H]+ calcd for C₄₉H₆₁F₃N₈O₈S₂ 1011.40786.found 1011.40793.

Benzyl (S)-2-amino-3,3-diphenylpropanoate (BQ)

(S)-2-amino-3,3-diphenylpropanoic acid (commercially available from, forexample, Fluorochem) (1.00 g, 4.144 mmol) and KOH (0.256 g, 4.559 mmol)were stirred in EtOH (40.0 mL) at it until complete dissolution ofsolids. Then, the reaction mixture was concentrated under vacuo toafford a white solid which was dissolved in dry DMF (40.0 mL) and benzylbromide (commercially available from, for example, Sigma Aldrich) (0.542mL, 4.559 mmol) was added. The mixture was stirred at rt overnight. Thereaction mixture was quenched with saturated solution NaHCO₃ andextracted with EA (50 mL×3). The reunited organic phases were washedwith brine (50 mL×2), dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to afford a colorless oil which was purified byflash chromatography on SiO₂ (PE/EA, 9:1 to 7:3) to give the titledcompound (0.325 g, 24% yield) as a clear oil, which turned white solidupon standing. ¹H NMR (400 MHz, CDCl₃): δ 7.53-7.16 (m, 13H), 7.17-7.05(m, 2H), 4.97 (dd, J=29.8, 12.2 Hz, 2H), 4.38-4.23 (m, 1H), 4.21-4.06(m, 1H). HRMS (EST) m/z [M+H]+ calcd for C₂₂H₂₁NO₂ 332.16451. found332.16494.

Tert-butyl(S)-2-(((S)-1-(benzyloxy)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(BR)

The titled compound can be prepared according to the process describedby Shibata, N. et al. J. Med. Chem. 2019, 61, 543-575. Under nitrogenatmosphere, to a solution of benzyl (S)-2-amino-3,3-diphenylpropanoate(BQ) (0.32 g, 0.965 mmol) and (tert-butoxycarbonyl)-L-proline(commercially available from, for example, Fluorochem) (0.291 g, 1.352mmol) in dry DMF (3.0 mL) were added HOBt monohydrate (0.207 g, 1.352mmol), DIPEA (0.336 mL, 1.931 mmol), and EDC HCl (0.259 g, 1.352 mmol)and the reaction mixture was stirred at rt overnight. The solution waspoured in ice-water, yielding a precipitate which was collected byfiltration and purified by flash chromatography on SiO₂ (PE/EA, 7:3 to6:4) to give the titled compound (0.408 g, 80% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 7.53-7.15 (m, 14H), 7.04 (dd, J=7.2, 2.3 Hz,2H), 5.50 (t, J=9.6 Hz, 1H), 5.02-4.85 (m, J=12.2 Hz, 2H), 4.37 (d,J=9.9 Hz, 1H), 4.30-0.07 (m, 1H), 3.38-3.00 (m, 2H), 2.25-1.52 (m, 4H),1.42 (s, 9H).

Benzyl (S)-3,3-diphenyl-2-((S)-pyrrolidine-2-carboxamido)propanoatehydrochloride (BS)

The titled compound can be prepared according to the process slightlymodified from that described by Shibata, N. et al. J. Med. Chem. 2019,61, 543-575. To a solution of tert-butyl(S)-2-(((S)-1-(benzyloxy)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(BR) (0.408 g, 0.772 mmol) in dry THF (2.0 mL) a solution of 4N HCl indioxane (2.5 mL) was added. The mixture was stirred at rt for 3 h. Thesolvent was evaporated to dryness and the residue was triturated withDEE and filtered off to afford the titled product (0.344 g, 96% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 10.87 (bs, 1H), 8.45 (bs,1H), 7.43-7.14 (m, 14H), 7.05 (d, J=3.8 Hz, 2H), 6.92 (s, 1H), 5.32 (s,1H), 5.00-4.79 (m, 2H), 4.64 (d, J=10.0 Hz, 1H), 4.38 (s, 1H), 3.39-3.02(m, 2H), 2.35 (s, 1H), 2.00-1.64 (m, 3H).

Benzyl(S)-2-((S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoate(BT)

The titled compound can be prepared according to the process describedby Shibata, N. et al. J. Med. Chem. 2019, 61, 543-575. Under nitrogenatmosphere, to a solution of benzyl(S)-3,3-diphenyl-2-((S)-pyrrolidine-2-carboxamido)propanoatehydrochloride (BS) (0.338 g, 0.727 mmol) and(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (commerciallyavailable from, for example, Fluorochem)(0.261 g, 1.018 mmol) in dry DMF(4.0 mL) were added HOBt monohydrate (0.156 g, 1.018 mmol), DIPEA (0.38mL, 2.181 mmol), and EDC HCl (0.195 g, 1.018 mmol) and the reactionmixture was stirred at rt overnight. The solution was poured inice-water, yielding a precipitate which was collected by filtration andpurified by flash chromatography on SiO₂ (PE/EA, 7:3 to 6:4) to give thetitled compound (0.36 g, 74% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.35-7.15 (m, 14H), 7.12-7.04 (m, 2H), 6.75 (d, J=8.7 Hz, 1H),5.44 (t, J=8.7 Hz, 1H), 5.15 (d, J=9.3 Hz, 1H), 5.01-4.85 (m, 1H),4.54-4.45 (m, 1H), 4.38 (d, J=8.7 Hz, 1H), 4.29-4.18 (m, 1H), 3.71-3.56(m, 1H), 3.43-3.28 (m, 1H), 2.18-2.08 (m, 1H), 1.89-1.65 (m, 7H), 1.44(s, 9H), 1.33-0.97 (m, 6H).

Benzyl(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoate(BV)

The titled compound can be prepared according to the process describedby Shibata, N. et al. J. Med. Chem. 2019, 61, 543-575. A solution of 4NHCl in dioxane (2.5 mL) was added to benzyl(S)-2-((S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoate(BT) (0.345 g, 0.516 mmol) and the mixture was stirred at rt for 3 h.The solvent was evaporated to dryness and the residue was trituratedwith DEE and filtered to afford benzyl(S)-2-((S)-1-((S)-2-amino-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoatehydrochloride (BU) (0.290 g, 93% yield) as a white solid. Under nitrogenatmosphere, to a solution of the obtained (BU)(0.290 g, 0.480 mmol) andN-(tert-butoxycarbonyl)-N-methyl-L-alanine (commercially available from,for example, Fluorochem) (0.136 g, 0.672 mmol) in dry DMF (3.0 mL) wereadded HOBt monohydrate (0.103 g, 0.672 mmol), DIPEA (0.25 mL, 1.439mmol), and EDC HCl (0.129 g, 0.672 mmol) and the reaction mixture wasstirred at rt overnight. The solution was then poured in ice-water,yielding a precipitate which was collected by filtration and purified byflash chromatography on SiO₂ (DCM/MeOH, 98:2) to give the titledcompound (0.287 g, 75% yield) as a colourless amorphous solid. ¹H NMR(400 MHz, CDCl₃): δ 7.34-7.15 (m, 14H), 7.07 (dd, J=6.6, 2.8 Hz, 2H),6.79-6.65 (m, 1H), 5.43 (t, J=8.6 Hz, 1H), 5.28 (s, 1H), 4.94 (s, 2H),4.74-4.59 (m, 1H), 4.54-4.44 (m, 2H), 4.39 (d, J=8.6 Hz, 1H), 3.72-3.59(m, 1H), 3.42-3.28 (m, 1H), 2.81 (s, 3H), 2.18-2.03 (m, 1H), 1.89-1.59(m, 7H), 1.51 (d, J=6.0 Hz, 9H), 1.36-1.29 (m, 3H), 1.28-0.86 (m, 6H).

(S)-2-((S)-1-((S)-2-((S)-2-((Tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoicacid (E3LB-5)

The titled compound can be prepared according to the process slightlymodified from that described by Shibata, N. et al. J. Med. Chem. 2019,61, 543-575. Under nitrogen atmosphere, to a solution of benzyl(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoate(BV) (0.280 g, 0.353 mmol) in dry MeOH (4.0 mL) were added 10% palladiumon carbon (0.056 g) and anhydrous ammonium formate (0.089 g, 1.412mmol). The reaction mixture was stirred at 40° C. for 3 h. Aftercooling, the reaction mixture was filtered over Celite and the filtratewas evaporated under vacuo yielding the titled compound as white solid(0.230 g, 98% yield). ¹H NMR (400 MHz, MeOD): δ 7.41-7.10 (m, 101H),5.19 (d, J=7.7 Hz, 1H), 4.66-4.30 (m, 5H), 3.85-3.73 (m, 1H), 3.68-3.56(m, 1H), 2.87 (s, 3H), 2.10-1.98 (m, 1H), 1.92-1.66 (m, 9H), 1.51 (s,9H), 1.39-1.24 (m, 5H), 1.15-0.96 (m, 2H). HRMS (ESI) m/z [M+H]+ calcdfor C₇H₅₀N₄O₇ 663.37523. found 663.37700.

Tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BW)

General Procedure III (overnight) was followed by using(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoicacid (E3LB-5)(0.057 g, 0.086 mmol),2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AH) (0.040 g, 0.086 mmol), DIPEA (0.06 mL, 0.343 mmol),and HATU (0.049 g, 0.128 mmol) in dry DMF (1.0 mL) to afford the titledcompound as white solid (0.061 g, 66% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 95:5). ¹H NMR (400 MHz,CDCl₃): a 7.94-7.86 (m, 1H), 7.57 (s, 1H), 7.34-7.13 (m, 11H), 6.94 (dd,J=16.8, 9.0 Hz, 1H), 6.50 (d, J=9.1 Hz, 1H), 6.18 (bs, 1H), 5.17 (t,J=9.1 Hz, 1H), 4.72-4.52 (m, 2H), 4.51-4.36 (m, 2H), 4.36-4.26 (m, 2H),3.91-3.78 (m, 6H), 3.70-3.58 (m, 4H), 3.57-3.49 (m, 6H), 3.43-3.24 (m,2H), 3.21-3.09 (m, 2H), 2.79 (s, 3H), 2.02-1.83 (m, 2H), 1.82-1.59 (m,7H), 1.49 (s, 9H), 1.41-1.25 (m, 7H), 1.03-0.76 (m, 2H). HRMS (ESI) m/z[M+Na]+ calcd for C₅₆H₇₃F₂N₇O₁₀S 1096.49999. found 1096.5010.

Tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BY)

General Procedure III (overnight) was followed by using(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoicacid (E3LB-5)(0.050 g, 0.075 mmol), tert-butyl(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamate(BI) (0.035 g, 0.075 mmol), DIPEA (0.05 mL, 0.302 mmol), and HATU (0.043g, 0.113 mmol) in dry DMF (1.5 mL) to afford the titled compound aswhite solid (0.043 g, 53% yield) following purification by flash columnchromatography on SiO₂ (DCM/MeOH, 95:5). ¹H NMR (400 MHz, CDCl₃): δ7.65-7.56 (m, 1H), 7.36-7.15 (m, 12H), 7.04-6.95 (m, 2H), 6.34-6.16 (m,2H), 5.28-5.18 (m, 1H), 4.85-4.73 (m, 1H), 4.72-4.56 (m, 3H), 4.46-4.33(m, 2H), 3.90-3.81 (m, 4H), 3.78-3.62 (m, 2H), 3.61-3.51 (m, 4H),3.36-3.16 (m, 4H), 3.05-2.91 (m, 1H), 2.79 (s, 3H), 2.10-1.81 (m, 4H),1.77-1.64 (m, 4H), 1.63-1.54 (m, 2H), 1.48 (s, 9H), 1.38-1.28 (m, 7H),1.24-1.10 (m, 2H). HRMS (ESI) m/z [M+H]+ calcd for C₅₆H₇₂F₂N₈O₉S1071.51838. found 1071.51999.

Tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BZ)

General Procedure III (overnight) was followed by using(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoicacid (E3LB-5)(0.038 g, 0.057 mmol), tert-butyl(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamate(BJ)(0.028 g, 0.057 mmol), DIPEA (0.04 mL, 0.227 mmol), and HATU (0.032g, 0.085 mmol) in dry DMF (0.5 mL) to afford the titled compound aswhite solid (0.031 g, 49% yield) following purification by flash columnchromatography on SiO₂ (DCM/MeOH, 98:2 to 97:3). HRMS (ESI) m/z [M+H]+calcd for C₅₈H₇₆F₂N₈O₉S 1099.54%8. found 1099.55025.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 24)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BW) (0.060 g, 0.056 mmol) in dry DCM (0.5 mL) was added a solution of4N HCl in dioxane (0.5 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (6 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5 to 94:6) yielding the titled compound (0.041 g, 75% yield) as whitesolid. HRMS (ESI) m/z [M+Na]+ calcd for C₅₁H₆₅F₂N₇O₈S 996.44756. found996.44769.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 25)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BY) (0.035 g, 0.033 mmol) in dry DCM (0.3 mL) was added a solution of4N HCl in dioxane (0.3 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (5 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,93:7 to 9:1) yielding the titled compound (0.010 g, 33% yield) as whitesolid. HRMS (ESI) m/z [M+Na]+ calcd for C₅₁H₆₄F₂N₈O₇S 993.44789. found993.44843.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 26)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BZ) (0.030 g, 0.027 mmol) in dry DCM (0.3 mL) was added a solution of4N HCl in dioxane (0.3 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (5 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5 to 93:7) yielding the titled compound (0.017 g, 63% yield) as whitesolid. HRMS (ESI) m/z [M+H]+ calcd for C₅₃H₆₈F₂N₈O₇S 999.49725. found999.49979.

(2R,3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide(Example 27)

General Procedure III (5 h) was followed by using4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoicacid (E3LB-6) (commercially available, for example, from Carbosynth)(0.021 g, 0.034 mmol),2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethan-1-aminehydrochloride (AH) (0.016 g, 0.034 mmol), DIPEA (0.024 mL, 0.137 mmol),and HATU (0.016 g, 0.043 mmol) in dry DMF (0.5 mL) to afford the titledcompound as white solid (0.030 g, 85% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 98:2). ¹H NMR (400 MHz,CDCl₃): δ 10.35 (s, 1H), 8.40 (d, J=8.2 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H),7.57 (s, 1H), 7.56-7.51 (m, 1H), 7.49 (s, 1H), 7.35 (t, J=7.6 Hz, 1H),7.28-7.24 (m, 1H), 7.23-7.10 (m, 4H), 6.92 (dd, J=17.3, 8.9 Hz, 1H),6.64 (bs, 1H), 4.78 (d, J=8.5 Hz, 1H), 4.57 (bs, 1H), 4.28 (s, 2H),4.16-4.07 (m, 1H), 3.93 (s, 3H), 3.86-3.79 (m, 6H), 3.70 (s, 8H),3.56-3.50 (m, 4H), 2.80 (s, 1H), 1.70-1.54 (m, 2H), 1.04 (s, 9H). HRMS(ESI) m/z [M+Na]+ calcd for C₅₀H₅₂Cl₂F₄N₆O₇S 1049.28236. found1049.28585.

(2R,3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide(Example 28)

General Procedure III (5 h) was followed by using4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoicacid (E3LB-6) (0.030 g. 0.049 mmol), tert-butyl(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamate(BI) (0.022 g, 0.049 mmol), DIPEA (0.034 mL, 0.195 mmol), and HATU(0.023 g, 0.061 mmol) in dry DMF (1.0 mL) to afford the titled compoundas white solid (0.033 g, 66% yield) following purification by flashcolumn chromatography on SiO₂(DCM/MeOH, 97:3). ¹H NMR (400 MHz, CDCl₃):δ 10.37 (s, 1H), 8.44 (d, J=8.4 Hz, 1H), 7.60-7.45 (m, 3H), 7.35-7.29(m, 1H), 7.29-7.26 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.19-7.07 (m, 3H),6.97 (td, J=9.1, 7.5 Hz, 1H), 6.90 (s, 1H), 6.52 (bs, 1H), 4.76 (d,J=8.4 Hz, 1H), 4.60 (s, 2H), 4.54 (t, J=8.6 Hz, 1H), 4.09 (t, J=10.4 Hz,1H), 3.94 (s, 3H), 3.86-3.77 (m, 4H), 3.55-3.49 (m, 4H), 3.42-3.34 (m,2H), 2.84-2.73 (m, 1H), 1.70-1.54 (m, 6H), 1.01 (s, 9H). HRMS (ESI) m/z[M+Na]+ calcd for C₅₀H₅₁C₂F₄N₇O₆S 1046.28269. found 1046.28517.

(2R,3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide(Example 29)

General Procedure III (4 h) was followed by using4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoicacid (E3LB-6)(0.031 g, 0.051 mmol), tert-butyl(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamate(BJ) (0.025 g, 0.051 mmol), DIPEA (0.035 mL, 0.204 mmol), and HATU(0.024 g, 0.063 mmol) in dry DMF (0.6 mL) to afford the titled compoundas white solid (0.044 g, 82% yield) following purification by flashcolumn chromatography on SiO₂ (DCM/MeOH, 99:1 to 98:2). ¹H NMR (400 MHz,CDCl₃): δ 10.38 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 7.59-7.45 (m, 3H), 7.32(t, J=6.8 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.19-7.07 (m, 3H), 6.97 (dd,J=16.6, 9.2 Hz, 1H), 6.90 (s, 1H), 6.36 (bs, 1H), 4.76 (d, J=8.4 Hz,1H), 4.57 (s, 2H), 4.54-4.48 (m, 1H), 4.09 (t, J=10.9 Hz, 1H), 3.94 (s,3H), 3.88-3.78 (m, 4H), 3.57-3.50 (m, 4H), 3.45-3.38 (m, 2H), 3.39-3.28(m, 2H), 2.85-2.74 (m, 1H), 1.70-1.49 (m, 6H), 1.47-1.32 (m, 4H), 1.01(s, 9H). HRMS (ESI)/z [M+Na]+ calcd for C₅₂H₅₅Cl₂F₄N₇O₆S 1074.31399.found 1074.31724.

Methyl 2-morpholinobenzo[d]thiazole-4-carboxylate (CA)

Methyl 2-isothiocyanatobenzoate (0.20 g, 1.035 mmol) and morpholine(0.09 mL, 1.035 mmol) were stirred under solvent free condition for 15min. Successively, DMF (4.0 mL) was added and the mixture was stirredfor further 10 min. Then, K₂CO₃ (0.143 g, 1.035 mmol), phenanthroline(0.019 g, 0.103 mmol), and palladium (II) acetate (0.014 g, 0.062 mmol)were added and the reaction mixture was stirred at 85° C. for 24 h. Thereaction mixture was diluted with water (40 mL) and extracted with EA(20 mL×3). The reunited organic phases were washed with brine (30 mL),dried over anhydrous Na₂SO₄, and concentered under reduced pressureaffording a crude residue which was purified by flash columnchromatography on SiO₂ (PE/EA, 9:1 to 8:2) to give the titled compound(0.028 g, 10% yield) as light-yellow solid. ¹H NMR (400 MHz, CDCl₃): δ7.93 (dd, J=7.8, 1.3 Hz, 1H), 7.76 (dd, J=7.8, 1.3 Hz, 1H), 7.11 (t,J=7.8 Hz, 1H), 3.96 (s, 3H), 3.89-3.79 (m, 4H), 3.74-3.64 (m, 4H); ¹³CNMR (101 MHz, CDCl₃): δ 170.02, 16 6.82, 151.78, 132.76, 128.61, 124.88,120.79, 120.67, 66.29 (2C), 52.12, 48.45 (2C).

2-Morpholinobenzo[d]thiazole-4-carboxylic acid (ARB-2)

To the solution of methyl 2-morpholinobenzo[d]thiazole-4-carboxylate(CA) (0.155 g, 0.557 mmol) in THF (2 mL) at 0° C. was added the solutionof lithium hydroxide monohydrate (0.233 g, 5.569 mmol) in water (2.0mL). The resulting mixture was stirred at it for 6 h. The organicsolvent was removed under vacuo, the residue was diluted with ice-water(4.0 mL) and the pH was slowly adjusted to 4-3 with 2N HCl yielding asolid which was collected by filtration and dried to afford the titledcompound as light-yellow solid (0.122 g, 83% yield). ¹H NMR (400 MHz,CDCl₃): δ 13.51 (bs, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.8 Hz,1H), 7.25-7.20 (m, 1H), 3.92-3.83 (m, 4H), 3.73-3.65 (m, 4H); ¹³C NMR(101 MHz, CDCl₃): δ 169.97, 166.34, 150.83, 129.76, 129.23, 125.54,122.25. 118.90, 65.97 (2C), 48.66 (2C).

N-(5-(((S)-1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)-2-morpholinobenzo[d]thiazole-4-carboxamide(Example 30)

General Procedure III (4 h) was followed by using2-morpholinobenzo[d]thiazole-4-carboxylic acid (ARB-2) (0.040 g, 0.151mmol),(2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (AZ) (0.088 g, 0.151 mmol), DIPEA (0.079 mL, 0.454 mmol),and HATU (0.072 g, 0.189 mmol) in dry DMF (0.5 mL) to afford the titledcompound as light-yellow solid (0.050 g, 42% yield) followingpurification by flash column chromatography on SiO₂ (DCM/MeOH, 98:2 to95:5). ¹H NMR (400 MHz, CDCl₃): δ 9.96-9.85 (m, 1H), 8.67 (s, 1H), 8.21(d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.48-7.30 (m, 5H), 7.18 (t,J=7.8 Hz, 1H), 6.38 (d, J=8.5 Hz, 1H), 5.15-5.01 (m, 1H), 4.74 (t, J=7.9Hz, 1H), 4.56 (d, J=8.6 Hz, 1H), 4.50 (s, 1H), 4.08 (d, J=11.4 Hz, 1H),3.88 (t, J=4.6 Hz, 4H), 3.72-3.57 (m, 6H), 3.51 (d, J=2.7 Hz, 2H),2.62-2.43 (m, 4H), 2.41-2.19 (m, 2H), 2.08 (dd, J=13.3, 8.3 Hz, 1H),1.87-1.73 (m, 2H), 1.69-1.58 (m, 2H), 1.46 (d, J=6.9 Hz, 3H), 1.03 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.33, 172.17, 169.73, 169.51, 165.53,150.28, 149.51, 148.51, 143.19, 131.60, 130.87, 130.75, 129.57 (2C),128.04, 126.45 (2C), 123.84, 122.72, 121.64, 70.06, 66.12, 58.43, 57.68,56.93, 48.81, 48.47, 38.92, 35.77, 35.51, 35.06, 29.23, 26.53, 23.02,22.23, 16.12. HRMS (ESI) m/z [M+H]+ calcd for C₄₀H₅₁N₇O₆S₂ 790.34150.found 790.3412.

Tert-butyl (6-(2-morpholinobenzo[d]thiazole-4-carboxamido)hexyl)arbamate(CB)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of 2-morpholinobenzo[d]thiazole-4-carboxylic acid(ARB-2) (0.050 g, 0.189 mmol), tert-butyl (6-aminohexyl)carbamate (0.041g, 0.189 mmol), and DIPEA (0.099 mL, 0.567 mmol) in dry DMF (0.5 mL) wasadded HATU (0.090 g, 0.236 mmol). Stirring was continued at rtovernight. The reaction mixture was diluted with water (20 mL) andextracted with EA (10 mL×3). The reunited organic layers were washedwith brine (15 mL), dried over anhydrous Na₂SO₄, and evaporated underreduced pressure to give a crude residue, which was purified by flashcolumn chromatography on SiO₂ (DCM/MeOH, 97:3) affording a yellow film(0.062 g, 71% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.83 (s, 1H), 8.27 (d,J=7.8 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 4.54 (bs,1H), 3.95-3.82 (m, 4H), 3.70-0.59 (m, 4H), 3.53 (dd, J=11.9, 6.5 Hz,2H), 3.18-3.01 (m, 2H), 1.73-1.64 (m, 2H), 1.54-1.41 (m, 13H), 1.41-1.31(m, 2H).

N-(6-Aminohexyl)-2-morpholinobenzo[d]thiazole-4-carboxamidehydrochloride (CC)

To the solution of tert-butyl(6-(2-morpholinobenzo[d]thiazole-4-carboxamido)hexyl)carbamate (CB)(0.055 g, 0.119 mmol) in dry DCM (0.5 mL) at 0° C. was added dropwisethe solution of 4N HCl in dioxane (0.5 mL). The mixture was stirred atit for 6 h. The solvent was evaporated to dryness and the crude residuewas triturated with DEE and filtered off to afford the titled compoundas a light-yellow solid (0.044 g, 92% yield). ¹H NMR (400 MHz, DMSO): δ9.74 (t, J=5.4 Hz, 1H), 7.98 (dd, J=7.7, 4.1 Hz, 2H), 7.89 (bs, 3H),7.20 (t, J=7.8 Hz, 1H), 3.87-3.74 (m, 4H), 3.70-3.56 (m, 4H), 3.40 (dd,J=12.4, 6.6 Hz, 2H), 2.75 (dd, J=13.8, 6.5 Hz, 2H), 1.67-1.49 (m, 4H),1.43-1.28 (m, 4H).

Tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((6-(2-morpholinobenzo[d]thiazole-4-carboxamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(CD)

General Procedure III (overnight) was followed by using(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoicacid (E3LB-5)(0.055 g, 0.083 mmol),N-(6-aminohexyl)-2-morpholinobenzo[d]thiazole-4-carboxamidehydrochloride (CC) (0.033 g, 0.083 mmol), DIPEA (0.058 mL, 0.331 mmol),and HATU (0.047 g, 0.124 mmol) in dry DMF (1.0 mL) to afford the titledcompound as white solid (0.061 g, 73% yield) following purification byflash column chromatography on SiO₂ (DCM/MeOH, 97:3 to 96:4). HRMS (ESI)m/z [M+H]+ calcd for C₅₅H₇₄N₈O₈S 1007.54231. found 1007.54274.

N-(6-((S)-2-((S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanamide)hexyl)-2-morpholinobenzo[d]thiazole-4-carboxamide(Example 31)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-((S)-1-((6-(2-morpholinobenzo[d]thiazole-4-carboxamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(CD) (0.050 g, 0.049 mmol) in dry DCM (0.5 mL) was added a solution of4N HCl in dioxane (0.5 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (6 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,97:3) yielding the titled compound (0.015 g, 33% yield) as white solid.HRMS (ESI) m/z [M+H]+ calcd for C₅₀H₆₆N₈O₆S 907.48988. found 907.48938.

Ethyl 1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxylate (ARB-3)

The mixture of ethyl 1H-imidazole-4-carboxylate (commercially availablefrom, for example, Sigma Aldrich) (0.24 g, 1.712 mmol),4-(4-bromothiazol-2-yl)morpholine (commercially available from, forexample, Fluorochem) (0.142 g, 0.571 mmol), and PdAc₂(PPh₃)₂ (0.022 g,0.028 mmol) in dry and degassed toluene (3.0 mL) was stirred at 150° C.in an Ace pressure tube (charged under nitrogen atmosphere) for 15 h.After cooling, the reaction mixture was evaporated to dryness andpurified by flash column chromatography on SiO₂ (PE/EA, 7:3 to 5:5) toafford the titled compound (0.105 g, 60% yield) as white solid. ¹H NMR(400 MHz, CDCl₃): δ 8.09-7.96 (m, 2H), 6.36 (s, 1H), 4.39 (q, J=7.1 Hz,2H), 3.91-3.74 (m, 4H), 3.57-3.46 (m, 4H), 1.39 (t, J=7.1 Hz, 3H). HRMS(ESI) m/z [M+H]+ calcd for C₁₃H₁₆N₄O₃S 309.10159. found 309.10191.

Ethyl2,5-dibromo-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxylate(ARB-4)

The mixture of ethyl 2,5-dibromo-1-H-imidazole-4-carboxylate (0.437 g,1.466 mmol), 4-(4-bromothiazol-2-yl)morpholine (commercially availablefrom, for example, Fluorochem) (0.146 g, 0.586 mmol), and PdAc₂(PPh₃)₂(0.044 g, 0.058 mmol) in dry and degassed toluene (3.0 mL) was stirredat 150° C. in an Ace pressure tube (charged under nitrogen atmosphere)for 16 h. After cooling, the reaction mixture was evaporated to drynessand purified by flash column chromatography on SiO₂(PE/EA, 8:2) toafford the titled compound (0.036 g, 13% yield) as light-yellow solid.¹H NMR (400 MHz, CDCl₃): δ 6.62 (s, 1H), 4.25 (q, J=7.1 Hz, 2H),3.99-3.62 (m, 4H), 3.62-3.22 (m, 4H), 1.26 (t, J=7.1 Hz, 3H). HRMS (ESI)m/z [M+H]+ calcd for Cl₃H₁₄Br₂N₄O₃S 464.92261. found 464.92235.

1-(2-Morpholinothiazol-4-yl)-1H-imidazole-4-carboxylic acid (CE)

To the solution of ethyl1-(2-morpholinothiazol-4-yl)-11-imidazole-4-carboxylate (ARB-3) (0.030g, 0.097 mmol) in THF (0.2 mL) and EtOH (0.1 ML) at 0° C. was added thesolution of lithium hydroxide monohydrate (0.008 g, 0.194 mmol) in water(0.3 mL). The resulting mixture was stirred at rt for 3 h. The organicsolvent was removed under vacuo, the residue was diluted with ice-water(5.0 mL) and the pH was slowly adjusted to 3 with 2N HCl yielding asolid which was collected by filtration and dried to afford the titledcompound as white solid (0.025 g, 92% yield). ¹H NMR (400 MHz, MeOD): δ8.26 (s, 1H), 8.08 (s, 1H), 6.87 (s, 1H), 3.97-3.74 (m, 4H), 3.68-3.43(m, 4H).

N-(6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxamide(Example 32)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxylic acid (CE)(0.027g, 0.098 mmol),4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (L) (0.044 g, 0.107 mmol), and DIPEA (0.055 mL, 0.318mmol) in dry DMF (1.0 mL) was added HATU (0.046 g, 0.122 mmol). Stirringwas continued at rt overnight. The reaction mixture was poured inice-water yielding a precipitate collected by filtration and thenpurified by flash column chromatography on SiO₂ (DCM/MeOH, 98:2 to 97:3)affording a yellow film (0.011 g, 17% yield). ¹H NMR (400 MHz, CDCl₃): δ9.33 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.33(s, 1H), 7.06 (d, J=6.8 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.34 (s, 1H),6.22 (s, 1H), 4.97-4.86 (m, 1H), 3.81 (s, 4H), 3.57-3.32 (m, 6H),3.29-3.14 (m, 2H), 2.93-2.62 (m, 3H), 2.20-2.03 (m, 1H), 1.62 (d, J=6.5Hz, 4H), 1.42 (s, 4H); ¹³C NMR (101 MHz, CDCl₃): δ 171.5, 170.5, 169.5,168.8, 167.7, 162.2, 147.0, 142.5, 137.4, 136.1, 135.0, 132.5, 119.5,116.8, 111.3, 109.9, 90.6, 66.0 (2C), 48.9, 48.0 (2C), 42.6, 38.9, 31.5,29.6, 29.0, 26.6, 26.5, 22.9. HRMS (ESI) m/z [M+H]+ calcd forC₃₀H₃₄N₈O₆S 635.23948. found 63523979.

2,5-Dibromo-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxamide(Example 33)

To the solution of ethyl2,5-dibromo-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxylate(ARB-4) (0.036 g, 0.077 mmol) in THF (0.2 mL) and EtOH (0.1 mL) at 0° C.was added the solution of lithium hydroxide monohydrate (0.0065 g, 0.154mmol) in water (0.3 mL). The resulting mixture was stirred at rt for 3h. The organic solvent was removed under vacuo, the residue was dilutedwith ice-water (5.0 mL) and the pH was slowly adjusted to 3 with 2N HClyielding a solid which was collected by filtration and dried to afford2,5-dibromo-1-(2-morpholinothiazol-4-yl)-1H-imidazole-4-carboxylic acid(CF) as yellow solid (0.032 g, 94% yield). Then, in an oven-driedround-bottom flask, under nitrogen atmosphere, to a stirred solution of(CF) (0.031 g, 0.071 mmol),4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (L) (0.029 g, 0.107 mmol), and DIPEA (0.055 mL, 0.318mmol) in dry DMF (1.0 mL) was added HATU (0.046 g, 0.071 mmol). Stirringwas continued at rt overnight. The reaction mixture was diluted withwater (20 mL) and extracted with EA (10 mL×3). The reunited organiclayers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, andevaporated under reduced pressure to give a crude residue, which waspurified by flash column chromatography on SiO₂ (DCM/MeOH, 96:4)affording a yellow solid (0.004 g, 7% yield). ¹H NMR (400 MHz, CDCl₃): δ8.01 (s, 1H), 7.58-7.42 (m, 1H), 7.15-6.97 (m, 2H), 6.91 (d, J=8.5 Hz,1H), 6.70 (s, 1H), 6.26 (t, J=5.2 Hz, 1H), 4.94 (dd, J=5.3, 12.2 Hz,1H), 3.95-3.79 (m, 4H), 3.62-3.47 (m, 4H), 3.42 (q, J=6.8 Hz, 2H),3.35-3.22 (m, 2H), 3.04-2.64 (m, 3H), 2.35-2.08 (m, 1H), 1.87-1.52 (m,8H). HRMS (ESI) m/z [M+Na]+ calcd for C₁₃H₁₄Br₂N₄O₃S 813.04245. found813.04210.

The human prostate cancer cell line, 22Rv1 has been reported to expressa high level of AR-V7. Thus, 22Rv1 was seeded at 50,000 cells/well on a24-well plate in quadruplicates and treated with test compound inconcentrations ranging up to 20 μM for four days. Standard culture mediawas RPMI-1640 supplemented with 10% fetal bovine serum. The testcompound initially was dissolved in DMSO at 50 mM. This stock solutionwas then diluted as needed for the indicated concentrations. At the endof the four-day period, cells were harvested using 1% trypsin andcounted using an automated cell counter.

The results as shown in Table 1 below demonstrate that the testcompounds decreased cell count in a concentration dependent manner.

TABLE 1 22Rv1 cell count decrease by compounds in the examples 22Rv1cell count decrease Examples at 10 uM for 48 hours 1 ++ 2 + 3 ++ 4 + 5 +6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 ++ 16 ++ 17 ++ 18 ++ 19 ++20 ++ 21 ++ 22 + 23 + 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 ++ 30 ++ 31+++ 32 + 33 + 34 ++ + - the cell count decreased between 0 and 20% ++ -the cell count decreased less than 50% +++ - the cell count decreased bymore than 50%

Immunoblot was carried out to determine the effect of the test compoundon AR-V7. 22Rv1 was plated at 200,000 cell/well on a 6-well plate andcultured as described with 10 μM test compound. After four days oftreatment, cells were harvested using a cell scraper and lysed in astandard fashion using SDS. After removing debris via centrifuge, 30 μgof protein were loaded onto SDS-PAGE gel. After electrophoresis, proteinwas transferred to a nylon membrane and ECL was carried out usingprimary antibody against AR-V7 (Thermofisher Scientific, cat#NC0752138). Protein bands were visualized using the commerciallyavailable Enhanced Chemiluminescence (ECL) kit (Thermofisher). As shownin FIG. 1 , the results demonstrated a dramatically decreased level ofAR-V7 protein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The following terms are used to describe the present disclosure. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the claims are usedherein to refer to one or to more than one (i.e., to at least one) ofthe grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or” as used herein and in the claims should beunderstood to mean “either or both” of the elements so conjoined, i.e.,elements that are conjunctively present in some cases and disjunctivelypresent in other cases. Multiple elements listed with “and/or” should beconstrued in the same fashion, i.e., “one or more” of the elements soconjoined. Other elements may optionally be present other than theelements specifically identified by the “and/or” clause, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, a reference to “A and/or B”, when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A only (optionally including elements other than B);in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, the term “or”should be understood to have the same meaning as “and/or” as definedabove. For example, when separating items in a list, “or” or “and/or”shall be interpreted as being inclusive, i.e., the inclusion of at leastone, but also including more than one, of a number or list of elements,and, optionally, additional unlisted items. Only terms clearly indicatedto the contrary, such as “only one of” or “exactly one of,” or, whenused in the claims, “consisting of,” will refer to the inclusion ofexactly one element of a number or list of elements. In general, theterm “or” as used herein shall only be interpreted as indicatingexclusive alternatives (i.e., “one or the other but not both”) whenpreceded by terms of exclusivity, such as “either,” “one of,” “only oneof,” or “exactly one of.”

The term “about” and the like, as used herein, in association withnumeric values or ranges, reflects the fact that there is a certainlevel of variation that is recognized and tolerated in the art due topractical and/or theoretical limitations. For example, minor variationis tolerated due to inherent variances in the manner in which certaindevices operate and/or measurements are taken. In accordance with theabove, the term “about” is normally used to encompass values within thestandard deviation or standard error.

In the claims, as well as in the specification, all transitional phrasessuch as “comprising,” “including,” “carrying,” “having,” “containing,”“involving,” “holding,” “composed of,” and the like are to be understoodto be open-ended, i.e., to mean “including without limitation”. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

It should also be understood, that although various compounds,compositions, and methods are described in “open” terms of “comprising,”“including,” or “having” various components or steps (interpreted asmeaning “including without limitation”), the compounds, compositions,methods, and devices can also “consist essentially of” or “consist of”the various components and steps, and such terminology should beinterpreted as defining essentially closed-member groups. This paragraphis not meant in any way to limit the meaning of “comprising,” “having,”or “including” (and other verb forms thereof) which are to beinterpreted as open-ended phrases meaning “including without limitation”consistent with patent law and custom. The intent of this paragraph ismerely to indicate that the closed-member groups defined by the“consisting of” or “consisting essentially of” language are lesserincluded groups within the open-ended descriptions and to providesupport for claims employing the “consisting of” or “consistingessentially of” language.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” can refer to both concurrent administration (administration oftwo or more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are co-administered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “effective” can mean, but is in no way limited to, thatamount/dose of the active pharmaceutical ingredient, which, when used inthe context of its intended use, effectuates or is sufficient toprevent, inhibit the occurrence, ameliorate, delay or treat (alleviate asymptom to some extent, preferably all) the symptoms of a condition,disorder or disease state in a subject in need of such treatment orreceiving such treatment. The term effective subsumes all othereffective amount or effective concentration terms, e.g., “effectiveamount/dose,” “pharmaceutically effective amount/dose” or“therapeutically effective amount/dose,” which are otherwise describedor used in the present application.

The effective amount depends on the type and severity of disease, thecomposition used, the route of administration, the type of mammal beingtreated, the physical characteristics of the specific mammal underconsideration, concurrent medication, and other factors which thoseskilled in the medical arts will recognize. The exact amount can beascertainable by one skilled in the art using known techniques (see,e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd,The Art, Science and Technology of Pharmaceutical Compounding (1999);Pickar, Dosage Calculations (1999); and Remington, The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,Williams & Wilkins).

The term “pharmacological composition,” “therapeutic composition,”“therapeutic formulation” or “pharmaceutically acceptable formulation”can mean, but is in no way limited to, a composition or formulation thatallows for the effective distribution of an agent provided by thepresent disclosure, which is in a form suitable for administration tothe physical location most suitable for their desired activity, e.g.,systemic administration.

The term “pharmaceutically acceptable” can mean, but is in no waylimited to, entities and compositions that do not produce an adverse,allergic or other untoward reaction when administered to a patient orsubject.

The term “pharmaceutically acceptable carrier” can mean, but is in noway limited to, any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration to apatient or subject. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Preferredexamples of such carriers or diluents include, but are not limited to,water, saline, ringer's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

The term “systemic administration” refers to a route of administrationthat is, e.g., enteral or parenteral, and results in the systemicdistribution of an agent leading to systemic absorption or accumulationof drugs in the blood stream followed by distribution throughout theentire body. Suitable forms, in part, depend upon the use or the routeof entry, for example oral, transdermal, or by injection. Such formsshould not prevent the composition or formulation from reaching a targetcell (i.e., a cell to which the negatively charged polymer is desired tobe delivered to). For example, pharmacological compositions injectedinto the blood stream should be soluble. Other factors are known in theart, and include considerations such as toxicity and forms which preventthe composition or formulation from exerting its effect. Administrationroutes which lead to systemic absorption include, without limitations:intravenous, subcutaneous, intraperitoneal, inhalation, oral,intrapulmonary and intramuscular.

The rate of entry of a drug into the circulation has been shown to be afunction of molecular weight or size. The use of a liposome or otherdrug carrier comprising the compounds of the instant disclosure canpotentially localize the drug, for example, in certain tissue types,such as the tissues of the reticular endothelial system (RES). Aliposome formulation which can facilitate the association of drug withthe surface of cells, such as, lymphocytes and macrophages is alsouseful.

The terms “patient” and “subject” are used throughout the specificationto describe a cell, tissue, or animal, preferably a mammal, e.g., ahuman or a domesticated animal, to whom treatment, includingprophylactic treatment, with the compositions according to the presentdisclosure is provided. For treatment of those infections, conditions ordisease states which are specific for a specific animal such as a humanpatient, the term patient refers to that specific animal, including adomesticated animal such as a dog or cat or a farm animal such as ahorse, cow, sheep, etc. In general, in the present disclosure, the termpatient refers to a human patient unless otherwise stated or impliedfrom the context of the use of the term.

The term “compound,” as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stermoisomers, including optical isomers (enantiomers) and othersteroisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives thereof where applicable, in context.Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. The termalso refers to any specific chemical compound in which one or more atomshave been replaced with one or more different isotopes of the sameelement. It is noted that in describing the present compounds, numeroussubstituents and variables associated with same, among others, aredescribed.

It is understood by those of ordinary skill that molecules which aredescribed herein are stable compounds as generally described hereunder.When the bond is shown, both a double bond and single bond arerepresented or understood within the context of the compound shown andwell-known rules for valence interactions.

As used herein, “derivatives” can mean compositions formed from thenative compounds either directly, by modification, or by partialsubstitution. As used herein, “analogs” can mean compositions that havea structure similar to, but not identical to, the native compound.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, cereblonis an E3 ubiquitin ligase protein that alone or in combination with anE2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase may be involved in polyubiquitination suchthat a second ubiquitin may be attached to the first; a third may beattached to the second, and so forth. Polyubiquitination marks proteinsfor degradation by the proteasome. However, there are someubiquitination events that are limited to mono-ubiquitination, in whichonly a single ubiquitin is added by the ubiquitin ligase to a substratemolecule. Mono-ubiquitinated proteins may not be targeted to theproteasome for degradation, but may instead be altered in their cellularlocation or function, for example, via binding other proteins that havedomains capable of binding ubiquitin. Further, different lysines onubiquitin can be targeted by an E3 to make chains. The most commonlysine is Lys48 on the ubiquitin chain. This is the lysine used to makepolyubiquitin, which is recognized by the proteasome.

As used herein, the terms “halo” or “halogen” means fluoro (F), chloro(Cl), bromo (Br) or iodo (I).

As used herein, the term “hydrocarbyl” means a compound which containscarbon and hydrogen and which may be fully saturated, partiallyunsaturated or aromatic and includes aryl groups, alkyl groups, alkenylgroups and alkynyl groups.

As used herein, the term “alkyl” means within its context a linear,branch-chained, or cyclic fully saturated hydrocarbon radical or alkylgroup, preferably a C₁-C₁₀, more preferably a C₁-C₆, alternatively aC₁-C₃ alkyl group, which may be optionally substituted. Examples ofalkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cyclohexyl,among others.

As used herein, the term “alkenyl” refers to linear, branch-chained, orcyclic C₂-C₁₀ (preferably C₂-C₆) hydrocarbon radicals containing atleast one C≡C bond.

As used herein, the term “Alkynyl” refers to linear, branch-chained, orcyclic C₂-C₁₀ (preferably C₂-C₆) hydrocarbon radicals containing atleast one C≡C bond.

As used herein, the term “alkylene” refers to a —(CH₂)_(n)— group(wherein n is an integer generally from 0-6), which may be optionallysubstituted. When substituted, the alkylene group preferably issubstituted on one or more of the methylene groups with a C₁-C₆ alkylgroup (including a cyclopropyl group or a t-butyl group), morepreferably a methyl group, but may also be substituted with one or morehalo groups, preferably from 1 to 3 halo groups or one or two hydroxylgroups, O—(C₁-C₆ alkyl) groups or amino acid sidechains as otherwisedisclosed herein. In certain embodiments, an alkylene group may besubstituted with a urethane or alkoxy group (or other group) which isfurther substituted with a polyethylene glycol chain (of from 1 to 10,preferably 1 to 6, often 1 to 4 ethylene glycol units) to which issubstituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, (3-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, praline, serine, threonine, valine, tryptophan, or tyrosine.

As used herein, a range of carbon atoms which includes C₀ means thatcarbon is absent and is replaced with H (or deuterium). Thus, a range ofcarbon atoms which is C₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and6 and for C₀, H (or deuterium) stands in place of carbon.

As used herein, the term “unsubstituted” means substituted only withhydrogen atoms.

As used herein, the term “substituted” or “optionally substituted” meansindependently (i.e., where more than a single substitution occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substituents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present invention, and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted N(C₀-C₆ alkyl)C(O)(OC₁-C₆ alkyl) group (which maybe optionally substituted with a polyethylene glycol chain to which isfurther bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present invention mayinclude, for example SiR₁R₂R₃ groups wherein each of R₁ and R₂ is asotherwise described herein, and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R³ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteraryl moiety) through an optionally substituted—(CH₂)_(m)— or, alternatively, an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m)— or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(n)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain. Preferred substituents on alkylene groups include halogen orC₁-C₆ (preferably C₁-C₃) alkyl groups, which may be optionallysubstituted with one or two hydroxyl groups, one or two ether groups(O—C₁-C₆ groups), up to three halo groups (preferably F), or a sidechainof an amino acid as otherwise described herein and optionallysubstituted amide (preferably carboxamide substituted as describedabove) or urethane groups (often with one or two C₀-C₆ alkylsubstituents, which group(s) may be further substituted). In certainembodiments, the alkylene group (often a single methylene group) issubstituted with one or two optionally substituted C₁-C₆ alkyl groups,preferably C₁-C₄ alkyl group, most often methyl or O-methyl groups or asidechain of an amino acid as otherwise described herein. In the presentinvention, a moiety in a molecule may be optionally substituted with upto five substituents, preferably up to three substituents. Most often,in the present invention moieties which are substituted are substitutedwith one or two substituents.

As used herein, the term “substituted” (each substituent beingindependent of any other substituent) also means within its context ofuse C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone,including sulfonamide, keto, carboxy, C₁-C₆ ester (oxyester orcarbonylester), C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁,nitro, cyano and amine (especially including a C₁-C₆ alkylene —NR₁R₂, amono- or di-C₁-C₆ alkyl substituted amines which may be optionallysubstituted with one or two hydroxyl groups). Each of these groupscontains unless otherwise indicated, within context, between 1 and 6carbon atoms. In certain embodiments, preferred substituents willinclude, for example, NH, NHC(O), O, ═O, (CH₂)_(m) (here, m and n are incontext, 1, 2, 3, 4, 5 or 6), S, S(O), SO₂ or NHC(O)NH, (CH₂)_(n)OH,(CH₂)_(n)SH, (CH₂)_(n)COOH, C₁-C₆ alkyl, (CH₂)_(n)O(C₁-C₆ alkyl),(CH₂)_(n)C(O)(C₁-C₆ alkyl), (CH₂)_(n)OC(O)(C₁-C₆alkyl),(CH₂)_(n)C(O)O(C₁-C₆ alkyl), (CH₂)_(n)NHC(O)R₁, (CH₂)_(n)C(O)NR₁R₂,(OCH₂)_(n)OH, (CH₂0)_(n)COOH, C₁-C₆ alkyl, (OCH₂)_(n)O(C₁-C₆ alkyl),(CH₂O)_(n)C(O)(C₁-C₆ alkyl), (OCH₂)_(n)NHC(O)R₁, (CH₂O)_(n)C(O)NR₁R₂,S(O)₂R_(s), S(O)R_(s) (R_(s) is C₁-C₆ alkyl or a (CH₂)_(m)NR₁R₂ group),NO₂, CN, or halogen (F, Cl, Br, I, preferably F or Cl), depending on thecontext of the use of the substituent. R₁ and R₂ are each, withincontext, H or a C₁-C₆ alkyl group (which may be optionally substitutedwith one or two hydroxyl groups or up to three halogen groups,preferably fluorine).

The term “substituted” also means, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group OC(O)NR₁R₂ group wherein R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

As used herein, the terms “aryl” and “aromatic,” in context, refer to asubstituted (as otherwise described herein) or unsubstituted monovalentaromatic radical having a single ring (e.g., benzene, phenyl, benzyl) orcondensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) andcan be bound to the compound according to the present invention at anyavailable stable position on the ring(s) or as otherwise indicated inthe chemical structure presented. Other examples of aryl groups, incontext, may include heterocyclic aromatic ring systems “heteroaryl”groups having one or more nitrogen, oxygen, or sulfur atoms in the ring(moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene,thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fusedring systems such as indole, quinoline, indolizine, azaindolizine,benzofurazan, etc., among others, which may be optionally substituted asdescribed above. Among the heteroaryl groups which may be mentionedinclude nitrogen-containing heteroaryl groups such as pyrrole, pyridine,pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole,triazole, triazine, tetrazole, indole, isoindole, indolizine,azaindolizine, purine, indazole, quinoline, dihydroquinoline,tetrahydroquinoline, isoquinoline, dihydroisoquinoline,tetrahydroiso-quinoline, quinolizine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine,imidazotriazine, pyrazinopyridazine, acridine, phenanthridine,carbazole, carbazoline, perimidine, phenanthroline, phenacene,oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine andpyridopyrimidine; sulfur containing aromatic heterocycles such asthiophene and benzothiophene; oxygen containing aromatic heterocyclessuch as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; andaromatic heterocycles comprising 2 or more hetero atoms selected fromamong nitrogen, sulfur and oxygen, such as thiazole, thiadizole,isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

As used herein, the term “substituted aryl” refers to an aromaticcarbocyclic group comprised of at least one aromatic ring or of multiplecondensed rings at least one of which being aromatic, wherein thering(s) are substituted with one or more substituents. For example, anaryl group can comprise a substituent(s) selected from: (CH₂)_(n)OH,(CH₂)_(n)O(C₁-C₆)alkyl, (CH₂)_(n)O(CH₂)_(n)(C₁-C₆)alkyl,(CH₂)_(n)C(O)(C₀-C₆) alkyl, (CH₂)_(n)C(O)O(C₀-C₆) alkyl,(CH₂)_(n)OC(O)(C₀-C₆) alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably substituted with a linkergroup attached to a ARB group, including a E3LB group), and/or at leastone of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), a naphthyl group, which may be optionally substituted, anoptionally substituted heteroaryl, preferably an optionally substitutedisoxazole including a methyl substituted isoxazole, an optionallysubstituted oxazole including a methyl substituted oxazole, anoptionally substituted thiazole including a methyl substituted thiazole,an optionally substituted isothiazole including a methyl substitutedisothiazole, an optionally substituted pyrrole including a methylsubstituted pyrrole, an optionally substituted imidazole including amethy limidazole, an optionally substituted benzimidazole ormethoxybenzyl-imidazole, an optionally substituted oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methyl substituted triazole group, an optionally substituted pyridinegroup, including a halo (preferably, F) or methyl substituted pyridinegroup or an oxapyridine group (where the pyridine group is linked to thephenyl group by an oxygen), an optionally substituted furan, anoptionally substituted benzofuran, an optionally substituteddihydrobenzofuran, an optionally substituted indole, indolizine orazaindolizine (2, 3, or 4-azaindolizine), an optionally substitutedquinoline, and combinations thereof.

As used herein, the term “carboxyl” denotes the group C(O)OR, wherein Ris hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl, whereas these generic substituentshave meanings which are identical with definitions of the correspondinggroups defined herein.

As used herein, the terms “heteroaryl” and “hetaryl” include, withoutlimitation, an optionally substituted quinoline (which may be attachedto the pharmacophore or substituted on any carbon atom within thequinoline ring), an optionally substituted indole (includingdihydroindole), an optionally substituted indolizine, an optionallysubstituted azaindolizine (2, 3 or 4-azaindolizine) an optionallysubstituted benzimidazole, benzodiazole, benzoxofuran, an optionallysub-stituted imidazole, an optionally substituted isoxazole, anoptionally substituted oxazole (preferably methyl substituted), anoptionally substituted diazole, an optionally sub-stituted triazole, atetrazole, an optionally substituted benzofuran, an optionallysubstituted thiophene, an optionally substituted thiazole (preferablymethyl and/or thiol substituted), an optionally substituted isothiazole,an optionally substituted triazole (preferably a 1,2,3-triazolesubstituted with a methyl group, a triisopopylsilyl group, an optionallysubstituted (CH₂)_(m)OC₁-C₆ alkyl group or an optionally substituted(CH₂)_(m)C(O)OC₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3-, or 4-pyridine) or a group according to the chemical structure:

wherein S^(C) is CHR^(SS), NR^(URE), or O;

-   -   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substi-tuted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a), wherein        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl).

R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally substitutedC₁-C₆ alkyl (preferably substituted with one or two hydroxyl groups orup to three halo groups), optionally substituted O—(C₁-C₆ alkyl)(preferably substituted with one or two hydroxyl groups or up to threehalo groups) or an optionally substituted —C(O)(C₁-C₆ alkyl) (preferablysubstituted with one or two hydroxyl groups or up to three halo groups);

R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a—C(O)(C₁-C₆ alkyl), each of which groups is optionally substituted withone or two hydroxyl groups or up to three halogen, preferably fluorinegroups, or an optionally substituted phenyl group, an optionallysubstituted heterocycle, for example piperidine, morpholine,pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,piperazine, each of which is optionally substituted, and

Y^(C) is N or C—R^(YC), wherein R^(YC) is H, OH, CN, NO₂, halo(preferably Cl or F), optionally substituted C₁-C₆ alkyl (preferablysubstituted with one or two hydroxyl groups or up to three halo groups(e.g. CF₃), optionally substituted O(C₁-C₆ alkyl) (preferablysubstituted with one or two hydroxyl groups or up to three halo groups)or an optionally substituted acetylenic group —C≡C—R_(a), wherein R_(a)is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl).

R^(PRO) is H, optionally substituted C₀-C₆ alkyl or an optionallysubstituted aryl, heteroaryl or heterocyclic group selected from thegroup consisting of oxazole, isoxazole, thiazole, isothiazole,imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,pyridine, piperidine, piperazine, morpholine, quinoline (each preferablysubstituted with a C₀-C₃ alkyl group, preferably methyl or a halo grouppreferably F or Cl), benzofuran, indolem indolizine, azaindolizine:

R^(PRO1) and R_(PRO2) are each independently H, an optionallysubstituted C₀-C₃ alkyl group or together form a keto group and each nis independently 0, 1, 2, 3, 4, 5 or 6 or an optionally substitutedheterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine,piperazine or morpholine (each of which groups when substituted arepreferably substituted with a methyl or halo).

As used herein, the terms “arylkyl” and “heteroarylalkyl” refer togroups that comprise both aryl or, respectively, heteroaryl as well asalkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ringsystems according to the above definitions.

As used herein, the term “arylalkyl” as used herein refers to an arylgroup as defined above appended to an alkyl group defined above. Thearylalkyl group is attached to the parent moiety through an alkyl groupwherein the alkyl group is one to six carbon atoms. The aryl group inthe arylalkyl group may be substituted as defined above.

As used herein, the terms “heterocycle” and “heterocyclic” refer to acyclic group which contains at least one heteroatom, i.e., O, N or S,and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroarylmoieties are subsumed under the definition of heterocycle, depending onthe context of its use. Exemplary heterocyclics include: azetidinyl,benzimidazolyl 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl,benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl,dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane,1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl,imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl,naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone,pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide,succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl,tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane amongothers.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, oxo (═O), and—SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxynitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

As used herein, the term “cycloalkyl” includes, without limitation,univalent groups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like.

As used herein, the term “substituted cycloalkyl” includes, withoutlimitation, a monocyclic or polycyclic alkyl group being substituted byone or more substituents, for example, amino, halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, orsulfa, whereas these generic substituent groups have meanings which areidentical with definitions of the corresponding groups as definedherein.

As used herein, the term “heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S, or P.

As used herein, the term “substituted heterocycloalkyl” refers to amonocyclic or polycyclic alkyl group in which at least one ring carbonatom of its cyclic structure being replaced with a heteroatom selectedfrom the group consisting of N, O, S, or P, and the group contains oneor more substituents selected from the group consisting of halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mereapto, or sulfa, whereas these generic substituent group havemeanings which are identical with definitions of the correspondinggroups as defined herein.

1. A compound having a chemical structure:ARB-Link-E3LB wherein ARB is an AR binding moiety that does not bind toa ligand binding domain, E3LB is an E3 ligase binding moiety, and Linkis a linker coupling the AR binding moiety to the E3 ligase bindingmoiety; and wherein the E3LB moiety is a structure selected from thegroup consisting of:

wherein in the E3LB moiety: X is CH₂, N, or O; D is a bond, aryl, orheteroaryl, wherein said aryl or heteroaryl is optionally substituted by1 or more halo, hydroxyl, nitro, CN, C₁₋₆ alkyl or C₁₋₆ alkoxyl; R¹⁰ isindependently optionally substituted alkyl or optionally substitutedcycloalkyl (e.g., cyclohexyl), wherein said optional substituents areselected from OH, halo, and NH₂; R¹¹ is independently optionallysubstituted alkyl or optionally substituted cycloalkyl, wherein saidoptional substituents are selected from alkyl, halogen, and OH; R¹² andR¹³ are independently hydrogen, optionally substituted alkyl (e.g.,methyl), and optionally substituted cycloalkyl; R²⁰ is selected is:

wherein B is aryl (e.g. phenyl); R²¹ is independently aryl (e.g.,phenyl) or heteroaryl, optionally substituted by mono-, di- ortri-substituted halogen (e.g., F or Cl); R²² is independently aryl(e.g., phenyl) or heteroaryl optionally substituted by mono-, di-, ortri-substituted halogen (e.g., F or Cl); R²³ is selected from alkyl,substituted alkyl, cycloalkyl, and substituted cycloalkyl, R²⁴ is H oralkyl; and E is para-substituted aryl (e.g., phenyl) optionallysubstituted by —OCH₃, —OCH₂CH₃, or halogen; and wherein the AR bindingmoiety is:

wherein in the AR binding moiety: A is 3-7 membered alicyclic with 0-4heteroatoms (e.g., morpholinyl) optionally substituted by 1 or morehalo, hydroxyl, or C₁₋₆ alkyl; B is aryl (e.g., phenyl), optionallysubstituted by 1 or more halo, hydroxyl, CN, OC₁₋₃ alkyl, CF₃, or C₁₋₆alkyl optionally substituted by 1 or more halo; R¹ is each independentlyselected from H, OH, CONH₂, CN, NH₂, OCH₃, CHF₂, CH₂F, CF₃, halo, andC₁₋₆ alkyl optionally substituted by 1 or more halo; and wherein thelinker (“L”) is a chemical structure represented by -A_(q)-, in which qis an integer greater than 1, and A is independently selected from thegroup consisting of a bond, CR^(L1)R^(L2), O, NR^(L3), CONR^(L3), CO,C₃₋₁₁ cycloalkyl, and heteroaryl (optionally substituted with 0-6 R^(L1)and/or R^(L2) groups), wherein R^(L1), R^(L2), and R^(L3) are eachindependently selected from the group consisting of H, halo, and C₁₋₈alkyl.
 2. (canceled)
 3. (canceled)
 4. The compound of claim 1, whereinthe linker comprises a structure selected from the group consisting of:


5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)10. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,andN-(6-((S)-2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanamido)hexyl)-2-morpholinobenzo[d]thiazole-4-carboxamide.11. A pharmaceutical composition, comprising: an effective amount of thecompound of claim 1, and a pharmaceutically acceptable carrier, additiveand/or excipient
 12. The pharmaceutical composition of claim 11, furthercomprising at least one additional anticancer agent.
 13. A method fortreating a disease state or condition in a patient wherein dysregulatedprotein activity is responsible for said disease or condition, saidmethod comprising administering an effective amount of the compoundaccording to claim
 1. 14. The compound according to claim 1, wherein theAR binding moiety is:

wherein A is:

B is:

and R¹ is each independently selected from H, halo, and C₁₋₆ alkyloptionally substituted by 1 or more halo.
 15. The compound according toclaim 1, wherein the linker comprises a chemical structure representedby -A_(q)-, in which q is an integer greater than 1, and A isindependently selected from the group consisting of a bond,CR^(L1)R^(L2), O, NR^(L3), and CONR^(L3), wherein R^(L1) and R^(L2), areeach independently selected from the group consisting of H and C₁₋₈alkyl, and wherein R^(L3) is H.
 16. The compound according to claim 1,wherein the E3LB moiety is a structure selected


17. The compound according to claim 1, wherein the E3LB moiety is:


18. The compound according to claim 17, wherein in the E3LB moiety, R¹⁰is optionally substituted cycloalkyl (e.g., cyclohexyl); R¹² and R¹³ areindependently optionally substituted alkyl (e.g., methyl); and R²⁰ is:

wherein B is phenyl.
 19. The compound according to claim 1, wherein theE3LB moiety is


20. The compound according to claim 19, wherein in the E3LB moiety: R²¹is aryl substituted by mono-, di- or tri-substituted halogen (e.g., F orCl); R²² is aryl substituted by mono-, di-, or tri-substituted halogen(e.g., F or Cl); R²³ is selected from alkyl; R²⁴ is H; and E ispara-substituted phenyl substituted by —OCH₃.